WO2011064790A1 - Nouveau procédé de production d'aliskirène, ses nouveaux intermédiaires et certains nouveaux composés - Google Patents

Nouveau procédé de production d'aliskirène, ses nouveaux intermédiaires et certains nouveaux composés Download PDF

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Publication number
WO2011064790A1
WO2011064790A1 PCT/IN2010/000086 IN2010000086W WO2011064790A1 WO 2011064790 A1 WO2011064790 A1 WO 2011064790A1 IN 2010000086 W IN2010000086 W IN 2010000086W WO 2011064790 A1 WO2011064790 A1 WO 2011064790A1
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Prior art keywords
compound
formula
preparation
salt
yield
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PCT/IN2010/000086
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English (en)
Inventor
Chandrashekar Ramarao
Patrick Thomas Michel
Rajasekhar Navakoti
Rama Devi Nandipati
Ramakrishna Rao
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Avra Laboratories Pvt. Ltd
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Publication of WO2011064790A1 publication Critical patent/WO2011064790A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/20—Free hydroxyl or mercaptan
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel process for preparation of a drug for hypertension and a renin inhibitor. More specifically, the present invention relates to processes for preparation of Aliskiren, its novel intermediates and certain novel compounds.
  • Renin inhibitors are known in the art. Aliskiren as renin inhibitor is also generally known in the art and is depicted structurally as below.
  • EP-A-1215201, WO2006/131304 and WO2008/119804 teaches alternative route to make Aliskiren.
  • a (I) reacting A (I) in a suitable solvent, preferably a mixture of methanol and water in the presence of hydrochloric acid, to give a compound A (II) of the formula
  • A(XV) The compound of formula A(XV) as obtained can be converted into its hemifumerate salt as per the procedure disclosed in US 6,730,798.
  • the present invention further encompasses certain novel intermediate compounds of Aliskiren which form part of this invention:
  • this invention describes novel processes for preparation of Aliskiren and its novel intermediates.
  • the invention further discloses certain novel intermediate compounds of Aliskiren and salts thereof.
  • the phrase 'salt' as used herein means and includes of any salt of the novel intermediate compounds of the invention that may be stable under normal storage conditions and easy to process in further reactions in the method of obtaining aliskiren.
  • A(XV) her embodiment a process for preparation of compound of the formula
  • Hydrochloric acid is added drop wise to a solution of A (I) dissolved in a mixture of methanol and water at ambient temperature.
  • the reaction mass is stirred and neutralized with potassium carbonate at ambient temperature.
  • the solvent is removed under reduced pressure and the crude product is azeotroped with toluene to remove traces of water.
  • Acetone is added to the crude product and stirred to obtain a solid that is filtered and washed with acetone.
  • the filtrate is concentrated under reduced pressure and azeotroped with toluene to yield A ( ⁇ ) as solid.
  • Trifluoroacetic acid is added to a solution of A (IV) containing acetonitriie and H20 at ambient temperature. The reaction mixture is then refluxed for 6 hrs. The solvent is removed under reduced pressure and the obtained crude compound is purified by column chromatography to yield A (V).
  • Lithium hexamethyldisilazide (LiHMDS) is added drop wise to a solution of A (V) and tetramethylethylenediamine in tetrahydrofuran at -78 °C over a period of 1 h.
  • the reaction mixture is stirred at the same temperature for 2 h and acetone is added drop wise at -78 °C for 1 hr and stirred at the same temperature for 2 more hours.
  • the reaction mixture is later quenched with 10% aqueous hydrochloric acid and diluted with ethyl acetate.
  • the organic layer is separated and the aqueous layer is extracted with ethyl acetate.
  • the combined organic layers are dried over sodium sulphate and concentrated under reduced pressure.
  • a (VI) Phosphorousoxychloride is added drop wise to a solution of A (VI) dissolved in pyridine at 10 °C for 30 min.
  • the reaction mixture is stirred at room temperature for 12 hrs.
  • pyridine is removed under reduced pressure and the residue is cooled to 0 °C.
  • Cold water is added and the pH is adjusted to 5.5 using 10% aqueous hydrochloric acid.
  • the compound is extracted into ethyl acetate and combined organic extracts are dried over sodium sulphate and removed under reduced pressure.
  • the obtained compound is purified by column chromatography with silica gel using hexane and ethyl acetate as solvent to yield A (VII).
  • a mixture of B (V), tetramethylethylenediamine in tetrahydrofuran is added dropwise to a solution of n-Butyllithium in tetrahydropyran at -78 °C over a period of 20 min.
  • the reaction mixture is stirred for 1 h and a solution of A (VIII) in tetrahydrofuran is added drop wise over a period of 20 min at -78 °C.
  • the reaction mixture is stirred at the same temperature for 1 hr and then quenched with IN aqueous hydrochloric acid (pH to ⁇ 7).
  • the reaction mixture is warmed to 0°C and extracted into ethyl acetate.
  • the organic layer is separated, dried over sodium sulphate and concentrated under vacuum.
  • the crude compound thus obtained is purified by column chromatography with silica gel using hexane and ethylacetate as solvent to yield A (IX).
  • Methanesulfonyl chloride is added drop wise to a solution of A (IX) in methylenechloride at -10 °C. Triethylamine is added drop wise for a period of 5 min. The progress of the reaction is monitored, after completion, the reaction mixture is diluted with methylenechloride and washed with water. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum. The crude compound obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield A (X).
  • Aqueous solution of potassium hydroxide is added to a solution of A ( ⁇ ) dissolved in a mixture of THF-water-methanol at 0°.C.
  • the reaction mixture is stirred at the same temperature for lOhrs.
  • the reaction mixture is extracted with ether and amberlite IR-120 resin (H 4 ) is added to the aqueous layer and stirred till PH ⁇ 4 is attained.
  • DCM is added to the aqueous layer and extracted with DCM.
  • the combined organic solutions are dried over sodium sulfate and concentrated under reduced pressure. The compound thus obtained is dried for lhr to afford hydroxy-acid intermediate.
  • A(XIV ) is dissolved in methylene chloride and Trifluoroacetic acid is added and stirred at room temperature for 3hours.After the reaction went to completion, solvents were removed under vaccum and the residue is dissolved in methanol. 10% Pd/C is added to the methanolic solution and hydrogenated in a parr shaker apparatus. The catalyst is filtered and the solvent is removed under reduced pressure to yield the product A(XV)
  • the hemifumarate salt of the title compound can be prepared as described in US 6,730,798, example Jl (comprising mixing with fumaric acid, dissolution in ethanol, filtration, evaporation of the obtained solution, redissolving of the residue in acetonitrile, inoculation with a. small amount of the title compound hemifumarate salt and isolation of the precipitating material).
  • Methanesulfonyl chloride is added drop wise to a solution of C(I) in methylene chloride at -10 °C.
  • Triethylamine is added drop wise for a period of 5 min.
  • the progress of the reaction is monitored, after completion, the reaction mixture is diluted with methylenechloride and washed with water.
  • the organic layer is separated, dried over sodium sulphate and concentrated under vacuum.
  • the crude compound obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield C (II).
  • reaction mixture is extracted into ethyl acetate (3 x 2000 ml).
  • organic layer is washed with saturated brine (2000 ml), dried over sodium sulphate and concentrated to give a yellow oil of A (III).
  • the crude product is dissolved in hexane and passed through 1.5 kg of silica gel. Hexane is removed under reduced pressure to give 330 g of A ( ⁇ ).
  • LiHMDS Lithium hexamethydisilazide
  • reaction mixture is later quenched with 10% aqueous hydrochloric acid (250 ml) and diluted with ethyl acetate (500 ml).
  • the organic layer is separated and the aqueous layer is extracted with ethyl acetate (500 ml).
  • the combined organic layers are dried over sodium sulphate and concentrated under reduced pressure.
  • the obtained residue is purified by column chromatography with silicagel to yield 30 g of A (VI).
  • a mixture of 2.69g (0.0098 mol) of B(V), 0.22g (0.0019 mol) of tetramethylethylenediamine in 5 ml of tetrahydrofuran is added drop wise to a solution of 6.0 ml (0.0098 mol) of n-Butyllithium (1.6 m) in 2.5 ml of tetrahydropyran at -78 °C over a period of 20 min.
  • the reaction mixture is stirred for 1 h and a solution of 2.5 g (0.0098 mol) of A (VIII) in 5 ml tetrahydrofuran is added drop wise over a period of 20 min at -78 °C.
  • reaction mixture is stirred at the same temperature for 1 hr and then quenched with IN aqueous hydrochloric acid (pH to ⁇ 7).
  • the reaction mixture is warmed to 0°C and extracted into ethyl acetate (20 ml).
  • the organic layer is separated, dried over sodium sulphate and concentrated under vacuum.
  • the crude compound thus obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield A (IX) (2.12g).
  • a (XI) 1.25 g (0.018 m) of sodium azide is added to a stirred solution of 2.0 g (0.0037 m) A (X) dissolved in 20 ml of dry N,N-dimethylformamide. 3.2 g (0.0094 m) of tetrabutylammoniumhydrogen sulfate is added to the reaction mixture and heated to 90 °C for 36 h. After completion of the reaction, solvent is removed under reduced pressure to give crude compound. The crude compound is purified by column chromatography to give A (XI) (0.4 g) as a thick liquid.
  • Methanesulfonyl chloride 0.82g (0.007moles) is added drop wise to a solution of C(I) 2.4g(0.005mol) in 24ml methylenechloride at -10 °C.
  • Triethylamine 0.789g (0.007mol) is added drop wise for a period of 5 min.
  • the progress of the reaction is monitored, after completion, the reaction mixture is diluted with methylenechloride and washed with water. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum.
  • the crude ompound obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield 2.7g C(II).

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

Abstract

L'invention concerne un nouveau procédé pour produire des inhibiteurs de rénine de type aliskirène. L'invention concerne également ses nouveaux composés intermédiaires et un procédé pour les fabriquer.
PCT/IN2010/000086 2009-11-30 2010-02-15 Nouveau procédé de production d'aliskirène, ses nouveaux intermédiaires et certains nouveaux composés WO2011064790A1 (fr)

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IN2940CH2009 2009-11-30
IN2940/CHE/2009 2009-11-30

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102746182A (zh) * 2012-07-27 2012-10-24 浙江普洛医药科技有限公司 一种阿利克伦的制备方法
US8703976B2 (en) 2011-10-02 2014-04-22 Milan Soukup Manufacturing process for 8-aryloctanoic acids such as Aliskiren

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0187702B1 (fr) * 1985-01-07 1990-03-14 Syntex (U.S.A.) Inc. Composés tensioactifs de N-(oméga, oméga-1-dialkoxy)- et N-(oméga, oméga-1-dialcénoxy)-alkyl-1 ammonium N,N,N-trisubstitué, leur préparation et compositions pharmaceutiques les contenant
WO2002088106A2 (fr) * 2000-11-17 2002-11-07 Medivir Ab Inhibiteurs de la cysteine protease
US6670507B2 (en) * 2000-12-14 2003-12-30 Speedel Pharma Ag Process for the preparation of aryloctanoyl amides
WO2008119804A1 (fr) * 2007-04-03 2008-10-09 Novartis Ag Nouveaux procédés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0187702B1 (fr) * 1985-01-07 1990-03-14 Syntex (U.S.A.) Inc. Composés tensioactifs de N-(oméga, oméga-1-dialkoxy)- et N-(oméga, oméga-1-dialcénoxy)-alkyl-1 ammonium N,N,N-trisubstitué, leur préparation et compositions pharmaceutiques les contenant
WO2002088106A2 (fr) * 2000-11-17 2002-11-07 Medivir Ab Inhibiteurs de la cysteine protease
US6670507B2 (en) * 2000-12-14 2003-12-30 Speedel Pharma Ag Process for the preparation of aryloctanoyl amides
WO2008119804A1 (fr) * 2007-04-03 2008-10-09 Novartis Ag Nouveaux procédés

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BARROS ET AL.: "Chemoselectivity in the Manipulation of Polyhydroxylated Compounds Derived from the Diastereoselective Dihydroxylation of Optically Active Allylic Enoate Alcohols.", TETRAHEDRON, vol. 52, no. 23, 1996, pages 7861 - 7874 *
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 114473-50-6 *
KUSZMANN ET AL.: "A detailed study of the acetalation of D-mannitol with acetone- sulfuric acid", CARBOHYDRATE RESEARCH, vol. 137, 1985, pages 276 - 281 *
KUSZMANN ET AL.: "The Synthesis of 1,2:5,6-Di-O-Isopropylidene-D-mannitol: A Comparative Study", CARBOHYDRATE RESEARCH, vol. 128, 1984, pages 87 - 99 *
KUWABARA ET AL.: "Design syntheses and mitochondrial complex I inhibitory activity of novel acetogenins mimics", EUROPEAN JOURNAL OF BIOCHEMISTRY, vol. 267, 2000, pages 2538 - 2546 *
MORPAIN ET AL.: "A Possible Model for a new Chiral Glyceride Synthesis. Part 1. Synthesis of 1-0-Aroyl-2-0-tosyl-sn-glycerols", JOURNAL OF CHEMICAL SOCIETY, PERKINS TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY, vol. 1979, no. 6, 1972, pages 1379 - 1383 *
WIGGINS L. F.: "The Acetone Derivative of Hexahydric Alcohols. Part I.", JOURNAL OF CHEMICAL SOCIETY, vol. 13, 1946, pages 13 - 14 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8703976B2 (en) 2011-10-02 2014-04-22 Milan Soukup Manufacturing process for 8-aryloctanoic acids such as Aliskiren
CN102746182A (zh) * 2012-07-27 2012-10-24 浙江普洛医药科技有限公司 一种阿利克伦的制备方法

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