WO2012078147A1 - Procédé de préparation d'intermédiaires utiles dans la production de l'aliskiren - Google Patents

Procédé de préparation d'intermédiaires utiles dans la production de l'aliskiren Download PDF

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Publication number
WO2012078147A1
WO2012078147A1 PCT/US2010/059449 US2010059449W WO2012078147A1 WO 2012078147 A1 WO2012078147 A1 WO 2012078147A1 US 2010059449 W US2010059449 W US 2010059449W WO 2012078147 A1 WO2012078147 A1 WO 2012078147A1
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Prior art keywords
methoxy
methoxypropyloxy
benzyl
isopropyl
benzene
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PCT/US2010/059449
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English (en)
Inventor
Manjunath Narayan Bhanu
Samir Naik
Rejoy Thomas
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Watson Laboratories, Inc.
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Priority to PCT/US2010/059449 priority Critical patent/WO2012078147A1/fr
Publication of WO2012078147A1 publication Critical patent/WO2012078147A1/fr

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    • 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
    • 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
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • the present invention relates to a process for preparing 4-[(2R)-2-X-methyl)-3- methylbutyl]-1 -nnethoxy-2-3(3-nnethoxypropoxy)-benzene wherein X is a leaving group and the use of this compound in the synthesis of aliskiren.
  • Aliskiren is an antihypertensive drug that is believed to act as a renin inhibitor. Aliskiren is also known as (2S, 4S, 5S, 7S)-N-(2-carbamoyl-2-methylpropoyl)-5-amino- 4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide or 5(S)-Amino-4(S)-hydroxy-2(S), 7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)- phenyl]-octanoic acid N-(2-carbamoyl-2,2-dimethyl-ethyl)-amide.
  • the chemical Formula (I) for aliskiren is shown below
  • Example 137 outlines the preparation of aliskiren hydrochloride
  • Example 83 outlines the preparation of aliskiren hemifumarate.
  • the aliskiren compound comprises 4 chiral carbon atoms
  • the synthesis of the enantiomerically pure compound is quite demanding.
  • TEKTURNA ® is a once-a-day oral tablet marketed by Novartis that contains aliskiren hemifumarate and hydrochlorothiazide for the treatment of hypertension.
  • the present invention relates to a method of preparing 4-[(2R)-2-(X-methyl)-3- methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene of the Formula (II):
  • X is a leaving group such as a halogen or an acyloxy moiety derived from an organic sulfonic acid.
  • One embodiment of the present invention for preparing 4-[(2R)-2-(X-methyl)-3- methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene of the Formula (II) comprises the steps of:
  • Y 1 and Y 2 are the same or different moieties and are either hydrogen, a C1-C6 alkyl, an unsubstituted or substituted aryl such as a monocyclic, bicyclic or tricyclic aryl moiety with 6 to 22 carbon atoms or an alkali metal to form a 4-methoxy-3-(3- methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative;
  • step (i) decarboxylating the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative prepared in step (i) to form a 4-methoxy-3-(3- methoxypropyloxy)-benzyl-2-isopropyl butanoic acid;
  • step (iii) resolving the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl butanoic acid prepared in step (ii) to obtain 4-methoxy-3-(3-methoxypropyloxy)-benzyl-(2R)-2- isopropyl butanoic acid; iv) reducing the 4-methoxy-3-(3-nnethoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid obtained in step (iii) to the corresponding alcohol, i.e., 4-[(2R)-2- (hydroxymethyl)-3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene; and
  • the 4-methoxy-3-(3-methoxypropyloxy)-benzyl halide employed in step (i) above may be formed by any method known in the art, however, one embodiment comprises the steps of (a) reacting a 3-hydroxy-4-methoxybenzyl alcohol with a 3-methoxy halopropane to form 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol and (b) halogenating the 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol to form 4-methoxy- 3-(3-methoxypropyloxy)-benzyl halide.
  • An additional embodiment of the present invention relates to a method for preparing 4-[(2R)-2-(halomethyl)-3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)- benzene of the Formula (II):
  • X is a halogen, preferably chloro, or bromo or iodo, p-Toluene sulfonyl (O- Tosyl), or Methylsulfonyl (O-Mesyl) comprising the steps of:
  • Y 1 and Y 2 are as previously defined and preferably wherein Y 1 and Y 2 are the same moiety and most preferably are a CrC 6 alkyl or benzyl to form a 4-methoxy-3-(3- methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative;
  • step (iii) decarboxylating the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative from step (iii) to form a 4-methoxy-3-(3-methoxypropyloxy)- benzyl-2-isopropyl butanoic acid;
  • step (iv) resolving the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl butanoic acid of step (iv) to isolate 4-methoxy-3-(3-methoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid;
  • X is a halogen, preferably chloro, bromo or iodo, p-Toluene sulfonyl (O-Tosyl), or Methylsulfonyl (O-Mesyl).
  • the present invention also relates to a process for preparing aliskiren or pharmaceutically acceptable salts thereof which employs 4-[(2R)-2-(X-methyl)-3- methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene of the Formula (II) prepared according to the processes as describe above.
  • Some methods for preparing aliskiren or pharmaceutically acceptable salts thereof from 4-[(2R)-2-(X-methyl)-3-methylbutyl]-1 - methoxy-2-(3-methoxypropoxy)-benzene of the Formula (II) are described in United States Patent No. 7,009,078 and WO 02/08172.
  • the present invention relates to a method for preparing 4-[(2R)-2-(X-methyl)-3- methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene of the Formula (II):
  • X is a leaving group.
  • the leaving group X may be a halogen such as chloro, bromo or iodo.
  • the leaving group may also be an acyloxy moiety derived from an organic sulfonic acid, such as an alkanesulfonyloxy, preferably a Ci to C 7
  • trifluoromethanesulfonyloxy or unsubstituted or substituted arylsulfonyloxy, preferably tolsulfonyloxy (tosyloxy).
  • the process for preparing 4-[(2R)-2-(X- methyl)-3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene of the Formula (II) comprises the steps of:
  • Y 1 and Y 2 are the same or different and are either hydrogen, a CrC 6 straight or branched alkyl, an unsubstituted or substituted aryl such as a monocyclic, bicyclic or tricyclic aryl moiety with 6 to 22 carbon atoms or an alkali metal to form a 4-methoxy-3- (3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative;
  • step (i) decarboxylating the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative from step (i) to form a 4-methoxy-3-(3-methoxypropyloxy)- benzyl-2-isopropyl butanoic acid;
  • step (iii) resolving the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl butanoic acid of step (ii) to isolate 4-methoxy-3-(3-methoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid;
  • step (iii) reducing the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid prepared in step (iii) to the corresponding alcohol, i.e., 4-[(2R)-2- (hydroxymethyl)-3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene; and
  • the reaction of the 4-methoxy-3-(3-methoxypropyloxy)-benzyl halide with an isopropyl malonate diester derivative is typically conducted in an organic solvent, preferably a non-polar organic solvent such as hexane, benzene, toluene, chloroform, diethyl ether, 1 ,4-dioxane or mixtures thereof.
  • an organic solvent preferably a non-polar organic solvent such as hexane, benzene, toluene, chloroform, diethyl ether, 1 ,4-dioxane or mixtures thereof.
  • the isopropyl malonate diester derivative is dissolved in the organic solvent and may be heated to facilitate the reaction. If heated, the reaction mixture should be maintained at least 10°C to 30°C below the boiling point of the organic solvent.
  • the reaction mixture may be heated to about 80°C to about 100°C, preferably about 85°C to about 95°C.
  • a strong base may be added to the solution to facilitate the
  • suitable bases include, but are not limited to, sodium methoxide and sodium ethoxide.
  • the 4-methoxy-3-(3- methoxypropyloxy)-benzyl halide is added to the isopropyl malonate diester derivative solution, preferably after the addition of the strong base.
  • the temperature of the reaction mixture should be maintained at least 10°C, preferably at least 20°C below the boiling point of the reaction solvent.
  • reaction mass After cooling, the reaction mass is quenched slowly with water while maintaining the temperature of the reaction mass during quenching below 20°C and preferably below 15°C. Once the reaction mass is quenched, the 4-methoxy-3-(3-methoxypropyloxy)- benzyl-2-isopropyl malonate diester derivative is isolated from the organic layer of the quenched reaction mass.
  • the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative may be isolated from the reaction mass by means commonly used in the chemical arts.
  • One embodiment for isolating the 4-methoxy-3-(3-methoxypropyloxy)- benzyl-2-isopropyl malonate diester derivative involves separating the upper organic layer of the quenched reaction mass and washing the organic layer with water and/or brine solution. The washed organic layer can be dried and concentrated to yield the 4- methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative.
  • the isopropyl malonate diester derivative employed in the present invention is preferably a compound of the Formula (III :
  • Y 1 and Y 2 are the same and are a CrC 6 straight or branched alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl or a monocyclic aryl such as benzyl.
  • the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative prepared in step (i) is decarboxylated to form 4-methoxy-3-(3- methoxypropyloxy)-benzyl-2-isopropyl butanoic acid.
  • the decarboxylation may occur by any means known in the chemical arts, however, in one embodiment of the present invention, the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl malonate diester derivative prepared in step (i) is added to a basic solution, such as an aqueous sodium hydroxide solution and refluxed until the reaction is completed.
  • An organic solvent may optionally be included in the refluxing reaction mass. If an organic solvent is included in the refluxing reaction mass, it preferable is a polar protic solvent such as ethanol, propanol, isopropanol, butanol or mixtures thereof.
  • reaction mass is cooled to about 20°C to about 40°C, preferably about 25°C to about 35°C and washed with an organic solvent, preferable an ether, such as isopropyl ether and then acidified with an acid, preferably a mineral acid such as hydrochloric or sulfuric acid.
  • an organic solvent preferably a polar aprotic solvent such as ethyl acetate,
  • the extracted organic solvent may be dried and concentrated by conventional drying and concentration means.
  • concentrated reaction mass may be dissolved in an organic solvent, preferably a polar aprotic solvent as defined above and combined with an aqueous base, and heated to no more than 10°C, preferably no more than 20°C and most preferably no more than 30°C below the boiling point of the organic solvent. The temperature is maintained while stirring the reaction mass for about 20 to about 50 hours, then cooled to about 20°C to about 40°C. Water and an organic solvent are added to the cooled reaction mass and stirred. The ratio of water to organic solvent added to the reaction mass is about 2:1 to about 8:1 , preferably about 3:1 to about 6:1 .
  • the organic solvent added to the reaction mass along with the water can be any type of organic solvent but is preferably a non- polar solvent and most preferably an organic ether such as isopropyl ether or diethyl ether.
  • an organic ether such as isopropyl ether or diethyl ether.
  • the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-2-isopropyl butanoic acid is resolved into 4-methoxy-3-(3-methoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid by conventional means known in the chemical arts.
  • 4-methoxy-3-(3- methoxypropyloxy)-benzyl-2-isopropyl butanoic acid may be resolved by enzymatic resolution, chromatographic methods, such as column chromatography or reaction with known stereo specific compounds such as the d or / form of tartaric acid, malic acid, mandelic acid, camphor 10-sulphonic acid or quinic acid.
  • the 4-methoxy-3-(3-methoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid should be substantially free of the corresponding S-isomer.
  • substantially free means the resolved and isolated mixture should contain at least 95% of 4-methoxy-3-(3-methoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid, preferably at least 97% and most preferably at least 99%.
  • the reduction can be accomplished by any means commonly used in the chemical arts, however, in one embodiment of the present invention, the reduction is accomplished by dissolving the 4-methoxy-3-(3- methoxypropyloxy)-benzyl-(2R)-2-isopropyl butanoic acid in an organic solvent, preferably a non-polar organic solvent such as hexane, benzene, toluene, chloroform, diethyl ether, 1 ,4-dioxane or mixtures thereof, followed by cooling the solution to a temperature below 30°C, preferably below 25°C and most preferably below 20°C.
  • a suitable reducing agent can be added to the reaction mixture.
  • Suitable reducing agents include, but are not limited, to lithium aluminum hydride, sodium hydride, sodium borohydride, hypophosphite, phosphorous acid, disiobutyl aluminum hydride and sodium bis (2-methoxyethoxy)aluminum hydride.
  • the temperature of the reduction reaction occurs between 10°C to about 40°C and preferably about 15°C to about 30°C.
  • the 4- [(2R)-2-(hydroxymethyl)-3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene may be isolated from the reaction mixture and the hydroxyl moiety is replaced with a leaving group X to form 4-[(2R)-2-(X-methyl)-3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)- benzene of the Formula (II):
  • One embodiment of the present invention wherein X is a halogen includes the step of dissolving the 4-[(2R)-2-(hydroxymethyl)-3-methylbutyl]-1 -methoxy-2-(3- methoxypropoxy)-benzene in an organic solvent, preferably a polar aprotic solvent such as ethyl acetate, dichloromethane, tetrahydrofuran, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide or mixtures thereof.
  • the reaction mixture is then cooled to about 20°C or less, preferably about 15°C or less and most preferably about 10°C or less, and the hydroxyl moiety is replaced with a halogen.
  • an organo phosphorous compound such as tripehnyl phosphine and a halogen source such as N-bromo succinimde are added to the cooled solution.
  • the temperature of the reaction solution after the addition of the halogen source is maintained about 20°C or less, preferably about 15°C or less and most preferably about 10°C or less for about 2-6 hours before being concentrated.
  • the resulting concentrate is mixed with an organic solvent, preferably a non-polar solvent such as hexane, benzene, toluene, chloroform, diethyl ether, 1 ,4-dioxane or mixtures thereof, and refluxed for a suitable period of time, such as 0.5 to 3 hours.
  • the 4-methoxy-3-(3-methoxypropyloxy)-benzyl halide employed in step (i) above may be formed by any method known in the art, however, one embodiment comprises the steps of: (a) reacting a 3-hydroxy-4-methoxybenzyl alcohol with a 3-methoxy halopropane to form 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol; and (b) halogenating the 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol to form 4-methoxy- 3-(3-methoxypropyloxy)-benzyl halide.
  • This embodiment of the present invention is shown in Scheme II:
  • Scheme II The reaction of 3-hydroxy-4-methoxybenzyl alcohol with 3 methoxy halopropane as shown in Scheme II can be conducted by dissolving the 3-hydroxy-4-methoxybenzyl alcohol in an organic solvent, preferable a polar aprotic solvent such as ethyl acetate, dichloromethane, tetrahydrofuran, acetone, dimethylformamide, acetonitrile,
  • a polar aprotic solvent such as ethyl acetate, dichloromethane, tetrahydrofuran, acetone, dimethylformamide, acetonitrile
  • the reaction mass may be heated to aid in the dissolution 3-hydroxy-4-methoxybenzyl alcohol. If heating is required, the reaction mass should be heated to no more than about 5°C, preferably no more than 10°C below the boiling point of the organic solvent.
  • a 3-methoxy halopropane preferably 3-methoxy bromoprane, is added to the solution and refluxed for about 5 to about 20 hours. After refluxing, the 4-methoxy-3-(3- methoxypropyloxy)-benzyl alcohol is isolated from the reaction mass by means commonly used in the chemical arts.
  • the 4-[(2R)-2-(X-methyl)-3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)- benzene of the Formula (II) can be used to prepare aliskiren or pharmaceutically acceptable salts thereof such as the hydrochloride or hemifumarate.
  • aliskiren or pharmaceutically acceptable salts thereof such as the hydrochloride or hemifumarate.
  • the aliskiren free base of Formula I may be converted to pharmaceutically acceptable acid additions salts be reacting the aliskiren free base with the desired acid such as hydrochloric acid or fumaric acid and isolating the resulting salt.
  • the aliskiren prepared in accordance with the present invention may be combined with at least one or more pharmaceutically acceptable excipients to prepare a dosage form for administration to a patient.
  • the dosage form may be a solid, liquid, powder, aerosol, syrup or injectable solution for oral, buccal, parental, ophthalmic, rectal, vaginal or transdermal routes of administration.
  • Pharmaceutically acceptable excipients that may be used to prepare the dosage forms are known in the art and include binders, fillers, diluents, lubricants, glidants, disintegrants, buffering agents, sweetening agents, stabilizers, solubilizers, surfactants and coating agents.
  • a preferred dosage form is a solid dosage form for oral administration such as a tablet or capsule.
  • the aliskiren prepared in accordance with the present invention may be administered to humans alone or combined with other drugs such as
  • hydrochlorothiazide to treat hypertension and other cardiovascular diseases.
  • reaction mixture was stirred while maintaining temperature between 0°C to 10°C for 2 hours.
  • the reaction mixture was slowly quenched into 1 .5 liters of brine solution while maintaining temperature below 5°C.
  • the temperature of the quenched solution was raised to about 30°C and stirred for 15 minutes.
  • the reaction mixture was allowed to settle, and the lower MDC layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 335 gm of 4-methoxy-3-(3- methoxypropyloxy)-benzyl bromide as an oil.
  • the acid solution was then extracted with 1 liter of ethyl acetate twice.
  • the ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain an oily residue.
  • the oily residue was dissolved in 1 .2 liter of dimethyl sulfoxide. 21 ml of water and 42 gm of sodium hydroxide were added to the dissolved oily residue, and the resulting reaction mixture was heated to about 155°C and stirred at this temperature for about 35 hours.
  • the reaction mixture was then cooled to about 30°C. 1 .7 liter of water and 400 ml of isopropyl ether were added and stirred for 15 minutes. Stirring was stopped, and the layers were separated.
  • the aqueous layer was back extracted with 400 ml of isopropyl ether thrice.
  • the isopropyl ether extracts were combined together and washed with 400 ml of water and then with 400 ml of brine solution.
  • the reaction mass was then concentrated under vacuum to obtain 176 gm of the product 4-[4-methoxy-3-(3-methoxypropyloxy)]-2-isopropyl butanoic acid as an oil.
  • the dried solids were then suspended in 100 ml of water and acidified with concentrated hydrochloric acid to a pH of about 1 to 1 .2.
  • the reaction mass was extracted with 100 ml of ethyl acetate.
  • the ethyl acetate extract was washed with 50 ml water and dried over anhydrous sodium sulfate.
  • the ethyl acetate extract was concentrated under vacuum to obtain the product 4-[4-methoxy-3-(3-methoxypropyloxy)]-(2R)-2-isopropyl butanoic acid as a brown oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne un procédé de préparation de 4-[(2R)-2-X-méthyl)- 3-méthylbutyl]-1-méthoxy-2-3(3- méthoxypropoxy)-benzène, X étant un groupe labile, et l'utilisation dudit composé dans la synthèse de l'aliskiren.
PCT/US2010/059449 2010-12-08 2010-12-08 Procédé de préparation d'intermédiaires utiles dans la production de l'aliskiren WO2012078147A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104058990A (zh) * 2013-03-21 2014-09-24 博瑞生物医药技术(苏州)有限公司 一种阿利克仑或其盐的分离分析方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007107317A1 (fr) * 2006-03-21 2007-09-27 Novartis Ag Sel d'aliskiren contenant de l'acide sulfurique
EP2062874A1 (fr) * 2007-11-20 2009-05-27 KRKA, tovarna zdravil, d.d., Novo mesto Procédé et intermédiaires pour la préparation d'aliskiren
EP2075244A1 (fr) * 2007-12-24 2009-07-01 DSMIP Assets B.V. Nouvelle voie pour la construction de blocs pour la fabrication d'inhibiteurs de la rénine
US20090318714A1 (en) * 2005-11-08 2009-12-24 John Mykytiuk Organic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090318714A1 (en) * 2005-11-08 2009-12-24 John Mykytiuk Organic compounds
WO2007107317A1 (fr) * 2006-03-21 2007-09-27 Novartis Ag Sel d'aliskiren contenant de l'acide sulfurique
EP2062874A1 (fr) * 2007-11-20 2009-05-27 KRKA, tovarna zdravil, d.d., Novo mesto Procédé et intermédiaires pour la préparation d'aliskiren
EP2075244A1 (fr) * 2007-12-24 2009-07-01 DSMIP Assets B.V. Nouvelle voie pour la construction de blocs pour la fabrication d'inhibiteurs de la rénine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104058990A (zh) * 2013-03-21 2014-09-24 博瑞生物医药技术(苏州)有限公司 一种阿利克仑或其盐的分离分析方法
CN104058990B (zh) * 2013-03-21 2017-03-15 博瑞生物医药（苏州）股份有限公司 一种阿利克仑或其盐的分离分析方法

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