[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2011070459A1 - Procédé de fabrication d'acides 8-aryloctanoïques énantiomériquement purs tels que l'aliskiren - Google Patents

Procédé de fabrication d'acides 8-aryloctanoïques énantiomériquement purs tels que l'aliskiren Download PDF

Info

Publication number
WO2011070459A1
WO2011070459A1 PCT/IB2010/055185 IB2010055185W WO2011070459A1 WO 2011070459 A1 WO2011070459 A1 WO 2011070459A1 IB 2010055185 W IB2010055185 W IB 2010055185W WO 2011070459 A1 WO2011070459 A1 WO 2011070459A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
alkyl
alkylaryl
arylalkyl
Prior art date
Application number
PCT/IB2010/055185
Other languages
English (en)
Inventor
Milan Soukup
Original Assignee
CarboDesign LLC
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 CarboDesign LLC filed Critical CarboDesign LLC
Publication of WO2011070459A1 publication Critical patent/WO2011070459A1/fr

Links

Classifications

    • 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
    • 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
    • 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
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • 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

Definitions

  • trans-configurated (2S,7S)- 2,7-diisopropyloct-4-enedioic acid or derivatives thereof have been used as a starting material in the synthesis of compounds of formula I.
  • C(5)- amino and C(4)-hydroxyl groups have been introduced via a three step reaction sequence, starting with halo lactonization of trans-double bond, then displacement of the halogen with azide followed by reduction or hydrogenation of the azide group.
  • trans-configurated double bond can be used.
  • the present invention discloses a novel efficient process for the manufacture enantiomerically pure compounds of general formula I, specifically of Aliskiren, shown in Scheme 1 :
  • the present invention claims a process for the preparation of a compound of the general formula I wherein R 1 represents hydrogen, linear or brunched C 1 -6 alkyl, C 1 -6 alkoxy-C 1 -6 alkyl, aryl, alkylaryl, arylalkyl, carbamoyl, trifluoracetyl, mesyl, tosyl, trifluoromethanesulfonyl, trialkylsilyl, preferably CH 3 OCH 2 CH 2 CH 2 -, acyl, formyl, R 4 represents hydrogen, alkyl, aryl, alkylaryl, arylalkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, alkylaryloxy, trialkylsilyl, trialkylsilyloxy, with heteroatom(s) substituted alkyl, aryl, alkylaryl, arylalkyl, preferably benzyl, mono-, di- or tri-meth
  • R 5 is hydroxy, linear or brunched Ci -6 alkyloxy, aryloxy, alkylaryloxy, arylalkyloxy, trialkylsilyloxy, halogen, preferably chlorine or bromine, -NH 2 , -NMe 2 or -NHCH 2 C(CH 3 )2CONH2 and
  • R 6 represents hydrogen, alkyl, aryl, alkylaryl, trialkylsilyl, alkylarylsilyl, with heteroatom(s) substituted alkyl, aryl, alkylaryl, arylalkyl, preferably benzyl, mono-, di- or tri-methoxybenzyl, or other O-protective group, in particular one which together with O forms an ester or carbonate, as -C(O)alkyl, -C(O)aryl, -C(O)alkylaryl, - C(O)arylalkyl, -C(O)Oalkyl, -C(O)Oaryl, -C(O)Oalkylaryl, -C(O)Oarylalkyl, preferably -C(O)Obenzyl (Cbz), -C(O)Otert.-butyl (BOC), formyl or acetyl; comprising following steps:
  • X represents -OH, linear or brunched Ci -6 -alkyloxy, aryloxy, alkylaryloxy, arylalkyloxy, trialkylsilyloxy or alkylarylsilyloxy,
  • halogen preferably chlorine or bromine
  • R 7 is linear or brunched C 1 -6 -alkyl, arylalkyl, preferably methyl, ethyl, tert. -butyl or benzyl,
  • R 8 and R 9 are independently from each other hydrogen, lower alkyl, arylalkyl, preferably -NH 2 , -NMe 2 or dibenzyl, or in particular R 8 and R 9 can form together with N a 5- or 6-membered heterocyclic ring which may contain one or more heteroatoms selected from N or O and, which can be unsubstituted or substituted, preferably such as 4-alkyl-oxazolidin-2-one-3-yl containing also a chiral center such as e.g. 4(R)- or 4(S)-benzyl-oxazolidin-2- one-3-yl,
  • R 10 and R 1 1 are independently from each other lower alkyl, arylalkyl or in particular R 10 and R 1 1 can form together with N and O a 5- or 6-membered heterocyclic ring which may contain one or more heteroatoms selected from N or O and, which can be unsubstituted or substituted, containing also a chiral center, preferably -NMeOMe and wherein the double bond is specifically c/ ' s-configurated, with a nitration agent containing NO 2 + -agent, preferably nitration agent defined such as NO 2 -Lvg, wherein Lvg is a leaving group, preferably NO 2 OAc or NO 2 BF 4 or Cerium ammonium nitrate (CAN), providing compound of formula I II
  • R 1 is the same as defined for the compound of formula I and R 3 is a metal containing group such as Li, Na, Mghalide (Grignard), -Znhalide, Mnhalide, cuprate -Cuhalide, -Cehalides, boronic acid as -B(OH) 2 , preferably -Li or -MgBr or -Mg ate complex, providing compound of formula either IV or IVa,
  • R 2 is N0 2 and
  • R 6 is hydrogen, alkyl, aryl, alkylaryl, trialkylsilyl, alkylarylsilyl, with heteroatom(s) substituted alkyl, aryl, alkylaryl, arylalkyi, preferably mono-, di- or tri-methoxybenzyl, or other O-protective group, in particular one which together with O forms an ester or carbonate, as -C(0)alkyl, -C(0)aryl, - C(0)alkylaryl, -C(0)arylalkyl, -C(0)Oalkyl, -C(0)Oaryl, -C(0)Oalkylaryl, - C(0)Oarylalkyl, preferably formyl, acetyl, -C(0)Obenzyl (Cbz) or -C(0)0-tert.- butyl (BOC); c) reaction of
  • IV IVa are first reduced with a reducing agent or hydrogenated. During this process C(8)-oxo and C(5)-nitro groups are, simultaneously or in separate steps, reduced. After appropriate protection of C(5)-amino group, compounds of formula VI or Via can be obtained,
  • R 1 , R 4 , R 6 are the same as defined for the compound of formula I and X is the same as defined for compound of formula II.
  • compounds of formula VI or Via are then subjected reaction with R 5 -H, wherein R 5 is the same as defined for the compound of formula I, preferably NH 2 CH 2 C(CH 3 ) 2 CONH 2 :
  • R 5 is the same as defined for the compound of formula I, preferably NH 2 CH 2 C(CH 3 ) 2 CONH 2 :
  • Either the lactone of formula VI can be opened directly with R 5 -H or compound of formula Via, after prior protection of C(4)-hydroxy group, subjected to a coupling reaction with R 5 -H as already reported in e.g. US 5.559.1 1 1 from Sep. 24, 1996.
  • the compounds can be present in the form of one possible isomer or a mixture of stereoisomers thereof, for example as enantiomerically pure compound or as isomer mixtures, such as racemates, diastereomer mixtures etc., depending on the number of asymmetric carbon atoms.
  • racemic compounds of formulas II, III or Ilia, IV or IVa or IVb and VI can be subjected at any stage of the synthesis to a resolution or separation step using (chiral) agent or including an enzymatic step or another separation method known as e.g. preparative HPLC or SMB etc..
  • a resolution or separation step using (chiral) agent or including an enzymatic step or another separation method known as e.g. preparative HPLC or SMB etc.
  • the resolution agent any chiral acid or base as commonly used for resolution of nitrogen- or alcohol- or carboxylate-containing compounds, can be used.
  • a characteristic of protective groups is that they can be removed readily (without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, or alternatively under physiological conditions (as e.g. enzymatic cleavage or formation).
  • Different protective groups can be selected so that they can be removed selectively at different stages of the synthesis while other protective groups remain intact.
  • the corresponding alternatives can be selected readily by a person skilled in the art from those given in the standard reference works mentioned in literature (as e.g. Mc Omie "Protective Groups in Organic Chemistry” or Green et al. "Protective Groups in Organic Synthesis") or in the description or in the claims or the Examples.
  • R 1 , R 4 , R 5 and R 6 are the same as defined above for the compound of formula I and the compounds of formula II, III, Ilia, IV, IVa, IVb and VI have the configuration as defined in Scheme 1 , can be carried out:
  • nitrogen function at the C(5)-atom and oxygen function at C(4)-atom are introduced simultaneously occurring formally as frans-addition to cis-configurated double bond: After initial cis-addition of NO 2 -cation to the double bond, in situ formed nitronium-cation, is spontaneously opened via an intramolecular mechanism leading exclusively to compound of formula III which can react further to compound of formula Ilia dependent on reaction conditions and reagent employed.
  • lactone formation can occur with high diastereoselectivity providing exclusively 5-membered either trans- or c/s-3,5- disubstituted lactone of formula III dependent on the functional group X employed in the nitration process as reported in analogy for iodolactonization in J. Org. Chem. 1989, 54, 1 178 and Liebigs Ann. Chem. 1990, 323.
  • the "nitration" agent containing NO 2 + -source can be any agent defined as NO 2 -Lvg, wherein Lvg is a leaving group.
  • Lvg is a leaving group.
  • cerium(IV)ammonium nitrate in Ac 2 O, methylenechloride or acetonitrile or CAN in the presence of NaNO 2 (J. Chem. Res. (S) 2003, 497, Bull. Inst. Chem. Res. Kyoto Univ. 1989, 67, 1 12, Tetrahedron 2004, 60, 397,
  • the compound of formula I la (Scheme 2) can also be subjected directly to nitration step under similar conditions as used above for compound of formula II. During this nitration step and subsequent work-up the triple bond is oxidized and hydrolyzed to carboxylic acid, the double bond nitrated as discussed leading to the compound of formula III.
  • the compound of formula V, wherein R 3 is metallic, especially an alkali or earth alkali metallic radical, as e.g. lithium, sodium, potassium or a group of the formula Mg- halogen, -Znhalogen, -Cer(halogen) 2 or boronic acid as -B(OH) 2 , preferably -Li or - MgBr or -Mg ate complex, is prepared from the corresponding aromatic halide (a compound of formula V, wherein R 3 is a halide, preferably bromide) and is used in situ in an inert solvent, such as THF etc. at a temperature range of -78° C to 0° C similar as reported in Novatis patent (p.
  • bortrifluoro etherate aluminium chloride, metal halide, preferably AI-, Zn-, lanthanide- and Bi-halides (Tetrahedron Letters 2003, 44, 2937, ibid. 2003, 44, 5343, Tetrahedron 2004, 60, 10843).
  • solvent aprotic organic solvent, preferably chlorinated hydrocarbons as methylenechloride or aliphatic hydrocarbons as hexane or heptane can be used.
  • the reduction or/and hydrogenation of 8-oxo group and 5-nitro groups in compounds of formula IV, IVa or IVb can be achieved either simultaneously or in separate steps.
  • the preferred reduction method is hydrogenation in the presence of homogeneous or heterogeneous hydrogenation catalysts or reduction with metal hydrides, preferably sodium or lithium borohydride or trialkylsilanes in the presence of acid, preferably triethylsilane in the presence of triflic or trifluoroacetic acid or Lewis acid as bortrifluoro etherate, ZnCI 2 , AICI 3 or TiCI 4 at reaction temperature between -78 C until reflux.
  • metal hydrides preferably sodium or lithium borohydride or trialkylsilanes in the presence of acid, preferably triethylsilane in the presence of triflic or trifluoroacetic acid or Lewis acid as bortrifluoro etherate, ZnCI 2 , AICI 3 or TiCI 4 at reaction temperature between -78 C until reflux.
  • reaction of the compounds of formula IV or IVa and VI or Via with a compound R 5 - H preferably NH 2 CH 2 C(CH 3 ) 2 CONH 2
  • R 5 - H preferably NH 2 CH 2 C(CH 3 ) 2 CONH 2
  • the lactones of formula IV or VI are directly reacted with NH 2 CH 2 C(CH 3 ) 2 CONH 2 as reported in EP-A-678 503 (p. 124, 130 and 131 ) or WO02/02508 (example H1 p. 35, preparation of J1 ) or US5.559.1 1 1 (example 83).
  • Coupling with free carboxylic acid can be carried out according to standard peptide coupling method as also described for this step in US 5,559,1 1 1 on page 22 - 25 or, as reported in analogues cases in Houben-Weyl, Methoden der organischen Chemie, 4 th Edition, Synthese von Peptidenl , Volume 15/11 1974, Volume IX, 1955, Volume E 1 1 , 1985, Gerge Thieme Verlag, Stuttgart, The Peptides, (e. Gross and J. Meienhofer) Volume 1 and 2, Academic Press, London 1979/1980 or M. Bodansky Principels of Peptide Synthesis, Springer Verlag, Berlin 1984.
  • the condensation of free carboxylic acid with amine can be carried out in the presence of one of the coupling agents as e.g. DCC or other dialkyl carbodiimides, carbonyldiimidazole, 1 ,2-oxazolinium compounds, e.g. 2-ethyl-5-phenyl-1 ,2-oxazolium-3 ' -suphonate and 2-tert.-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g.
  • one of the coupling agents as e.g. DCC or other dialkyl carbodiimides, carbonyldiimidazole, 1 ,2-oxazolinium compounds, e.g. 2-ethyl-5-phenyl-1 ,2-oxazolium-3 ' -suphonate and 2-tert.-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e
  • the compound of formula III (Scheme 1 ) can be subjected a reduction and/or hydrogenation, either in one or in several reaction steps, providing known bicyclic compound of formula XII which has been already used in the synthesis of compound of formula I (Aliskiren) as reported in US Patent Appl. 61/279.995 from October 29, 2009, WO 2007/045420 from April, 26 2007, WO 2008/1 19804 from Oct. 9, 2008 and WO 2008/155338 from Dec. 24, 2008)).
  • nitrene prepared in situ a) either by thermal decomposition of alkyl- or aryl- or arylakyl-azide, preferably benzyl azide, Mesyl-, Tosyl-azide, or alkyl azidoformiate such as N 3 COOMe or NsCOObenzyl or N 3 COOtert.-butyl, or acyl azide such as AcN 3 or PhCON 3 (Tetrahedron 1990, 46, 191 1 or Tetrahedron Letters 1964, 52, 3953 or Can. J. Chem. 1968, 46, 3333)
  • alkane or arene sulfonyl oxycarbamate such as alkyl- or benzyl- or tert.-butyl-OC(O)NH Mesyl or -Tosyl or -Nosyl or H2NSO3CH2CCI3 in the presence of Phl(OAc) 2 and Rh-catalyst (Can. J. Chem. 1971 , 49, 2610 or Tetrahedron Lett. 2009, 50, 3329 or Angew. Chem. Int. Ed. 2008, 47, 8703 or J. Org. Chem. 2005, 70, 3296 or J. Amer. Chem. Soc. 2002, 124, 13672) in inert organic solvent, preferably methylenechloride, THF under room or elevated temperature,
  • X is the same as defined for compound of formula II and R 12 is hydrogen, alkyl, aryl, alkylaryl, arylalkyl, trialkylsilyl, hydroxy, alkoxy, arylalkyloxy, with heteroatom(s) substituted alkyl, aryl, alkylaryl, arylalkyl, preferably benzyl, mono-, di- or tri- methoxybenzyl, or other N-protective group, in particular one which together with N forms an amide or carbamate as -C(O)alkyl, -C(O)aryl, -C(O)alkylaryl, -C(O)arylalkyl, - C(O)Oalkyl, -C(O)Oaryl, -(O)COalkylaryl, -C(O)Oarylalkyl, preferably formyl, acetyl, trifluoroacetyl, -C(O)Obenzyl (
  • R 2 is NR 4 R 12 wherein R 4 and R 12 are independently from each other arylalkyl, preferably benzyl, mono-, di- or trimethoxybenzyl, or trialkylsilyl or other N-protective group, in particular one which together with N forms an amide or carbamate as -C(0)alkyl, - C(0)aryl, -C(0)alkylaryl, -C(0)arylalkyl, -C(0)Oalkyl, -C(0)Oaryl, -C(0)Oalkylaryl, - C(0)Oarylalkyl, preferably formyl, acetyl
  • R 12 is hydrogen, lower alkyl, alkylaryl, arylalkyl, trialkylsilyl, -OH, -Oalkyl, -Oaryl, - Oalkylaryl, -Oarylalkyl, -Otrialkylsilyl, with heteroatom(s) substituted -alkyl, aryl, alkylaryl, arylalkyl, preferably methoxy, benzyl, mono-, di- or tri-methoxybenzyl, or other N- protective group, in particular one which together with N forms an amide or carbamate, as -C(O)alkyl, -C(O)aryl, -C(O)alkylaryl, -C(O)arylalkyl, -C(O)Oalkyl, -C(O)Oaryl, - C(O)Oalkylaryl, -C(O)Oarylalkyl, preferably -C(O)Obenzyl
  • Both compounds of formula III or XII can be reacted with compound of formula V providing compound of formula IV which is known intermediate in the synthesis of the final compound of formula I (Aliskiren) as reported in US Patent Appl. 61/279.995 from October 29, 2009, WO 2007/045420 from April, 26 2007, WO 2008/1 19804 from Oct. 9, 2008 and WO 2008/155338 from Dec. 24, 2008.
  • the starting compounds of formula II and I la can be prepared in many ways, preferably as shown in Scheme 2:
  • cis-compound of formula VII is isomerically pure in order to obtain pure cis- configurated compound of formula II.
  • compound of formula VIII isopropylmalonate or isopropyl malodinitrile can be used which can be more easily deprotonated, preferably with e.g. sodium hydride in THF or even in aqueous sodium hydroxide solution under phase transfer conditions (PTC), and then alkylated in the same way.
  • the alkylation product has to be subjected to a decarboxylation step either on a stage of free carboxylic acid or ester thereof as reported by e.g. Krapcho in Tetrahedron Letters 1967, 8, 215.
  • Enantiomerically pure c/s-compound of formula II with configuration as shown in Schemes 1 and 2 can be prepared by a classical racemate resolution as e.g. reported in WO 2007/048620 from Mai 3, 2007.
  • 4(R)-or 4(S)-benzyl- oxazolidin-2-one-3-yl can be deprotonated with a strong organic base as LDA or LiHMDS and the enolate alkylated with c/s-1 ,4-dibromobut-2-ene.
  • cis-configurated compound of formula II can also be prepared by analogous method as reported above using Evan chiral auxiliary wherein, instead of cis- 1 ,4-dibromo-but-2-ene, compound of formula Vila, preferably 1 ,4-dibromo-but-2-yne or Mesylate or Tosylate derived from but-2-yne-1 ,4-diol, has been used and after alkylation step, the triple bond in compound of formula XIII then subjected to partial hydrogenation, preferably with Lindlar catalyst (Scheme 2).
  • a chiral acetylene of formula IX wherein Z is halogen, preferably chlorine or bromine, is reacting with alkali or earth alkali metal, preferably lithium, magnesium or Sn, Al, Zr or In, providing corresponding organometallic compound which in situ can be subjected in the presence of catalytic amount of transition metals and phospine ligands, preferably Palladium complexes as e.g.
  • Chiral compound of formula IX can be prepared from inexpensive known chiral alcohol of formula IX, wherein Z is hydroxy, -OMesyl, -OTosyl or -OS0 2 CF 3 , by enzymatic resolution of the corresponding racemate.
  • the enantiomerically pure compound of formula lla can be selectively oxidized with e.g. periodate in the presence of various transition metal catalysts such as Ru0 2 giving the compound of formula II which can be used as discussed above.
  • reaction mixture After stirring at the same temperature for 1 hr the reaction mixture was wormed to 0° C, then again cooled down to -70° C and cis- 1 ,4-dibromo-but-2-ene (4.5 g) in THF (10 ml) was slowly added, the reaction mixture shortly stirred at -70° C, then warmed to rt and stirred for 7 hrs and finally poured on mixture of ice water and saturated sodium chloride solution (400 ml, 1 :1 ).

Landscapes

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

Abstract

La présente invention porte sur un nouveau procédé de fabrication et de nouveaux intermédiaires utiles dans la synthèse de composés pharmaceutiquement actifs, en particulier d'inhibiteurs de la rénine, tels que l'aliskiren. L'invention porte sur une préparation d'acides 8-aryloctanoïques énantiomériquement purs représentés par la formule générale (I) à partir d'un intermédiaire clé aisément disponible, un cis-diacide chiral de formule (II), d'aziridine de formule (XI) et d'un composé monocyclique de formule (III). Formule (I) Formule (II) Formule (III) Formule (XI).
PCT/IB2010/055185 2009-12-07 2010-11-16 Procédé de fabrication d'acides 8-aryloctanoïques énantiomériquement purs tels que l'aliskiren WO2011070459A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28361609P 2009-12-07 2009-12-07
US61/283,616 2009-12-07

Publications (1)

Publication Number Publication Date
WO2011070459A1 true WO2011070459A1 (fr) 2011-06-16

Family

ID=44082656

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/055185 WO2011070459A1 (fr) 2009-12-07 2010-11-16 Procédé de fabrication d'acides 8-aryloctanoïques énantiomériquement purs tels que l'aliskiren

Country Status (2)

Country Link
US (1) US20110137047A1 (fr)
WO (1) WO2011070459A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20131170A1 (it) * 2013-07-11 2015-01-12 Zach System Spa Processo di preparazione di acidi 8-arilottanoici

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2551260A1 (fr) * 2011-07-28 2013-01-30 Chemo Ibérica, S.A. Procédé chimique pour l'ouverture de composés cycliques
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
WO2007045420A2 (fr) * 2005-10-17 2007-04-26 Novartis Ag Composes organiques
WO2008155338A2 (fr) * 2007-06-19 2008-12-24 Novartis Ag Composés organiques
US20090221848A1 (en) * 2005-10-28 2009-09-03 Reuter Chemischer Apparatebau Kg Process for preparing octenoic acid derivatives
EP2189442A1 (fr) * 2008-11-20 2010-05-26 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé et intermédiaires pour la préparation d'aliskiren

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY119161A (en) * 1994-04-18 2005-04-30 Novartis Ag Delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides with enzyme especially renin inhibiting activities

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007045420A2 (fr) * 2005-10-17 2007-04-26 Novartis Ag Composes organiques
US20090221848A1 (en) * 2005-10-28 2009-09-03 Reuter Chemischer Apparatebau Kg Process for preparing octenoic acid derivatives
WO2008155338A2 (fr) * 2007-06-19 2008-12-24 Novartis Ag Composés organiques
EP2189442A1 (fr) * 2008-11-20 2010-05-26 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé et intermédiaires pour la préparation d'aliskiren

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20131170A1 (it) * 2013-07-11 2015-01-12 Zach System Spa Processo di preparazione di acidi 8-arilottanoici
WO2015003988A1 (fr) * 2013-07-11 2015-01-15 Zach System S.P.A. Procédé de préparation d'acides 8-aryloctanoïques

Also Published As

Publication number Publication date
US20110137047A1 (en) 2011-06-09

Similar Documents

Publication Publication Date Title
TWI288128B (en) Asymmetric synthesis of pregabalin
KR101294432B1 (ko) 레닌 억제제 합성의 중간체로서의3-알킬-5-(4-알킬-5-옥소-테트라히드로푸란-2-일)피롤리딘-2-온 유도체
JP2018523633A (ja) ブリバラセタムを製造する方法
CN112739683B (zh) 布瓦西坦的制备方法及其中间体
US8203005B2 (en) Manufacturing process for enantiomerically pure 8-aryloctanoic acids as Aliskiren
RU2418785C2 (ru) Способ получения ингибиторов ренина
AU2008265181A1 (en) Process for the synthesis of intermediates of renin inhibitors such as aliskiren
WO2011070459A1 (fr) Procédé de fabrication d'acides 8-aryloctanoïques énantiomériquement purs tels que l'aliskiren
Ono et al. Preparation of pyrroles having long alkyl chains from nitroalkenes.
EP2546243B1 (fr) Procédé de préparation de l'aliskirène
AU2006299097B2 (en) Sythesis of renin inhibitors involving a cycloaddition reaction
CN108752253B (zh) 一种多元氮杂环状非天然手性氨基酸及其合成方法
JPH11501313A (ja) スピロ縮合アゼチジノンの触媒エナンチオ選択的合成
JP3084345B2 (ja) 光学活性な２−プロピルオクタン酸の製造方法
US5449813A (en) Phenylethanolamino- and phenylethanolaminomethyl-tetralines, process for the preparation thereof, intermediates in said process and pharmaceutical compositions containing them
WO2011048523A1 (fr) Procédé pour la fabrication d'acides aryloctanoïques énantiomériquement purs tels que l'aliskiren
EP0769003B1 (fr) Diaminopropanols derives d'un amino-acide
CN112174837B (zh) 一种合成(R)-4-甲氧基-α-甲基苯乙胺的方法
CN112920053B (zh) 一种手性α-甲基芳乙胺的制备方法
Chang et al. Synthesis of (1R, 3R, 5S)-1-Amino-3-(hydroxymethyl) bicyclo [3.1. 0] hexane as a Precursor for the Synthesis of Carbocyclic Nucleosides
Ballini et al. Synthesis of ω‐Nitro Acids and ω‐Amino Acids by Ring Cleavage of α‐Nitrocycloalkanones
CN111087405B (zh) 一种不对称合成石蒜科生物碱(+)-γ-lycorane的方法
JPS60199884A (ja) ベスタチン類の新規製造法
JP3088328B2 (ja) 光学活性２−フェニル−２−（２’−ピペリジニル） 酢酸エステル誘導体の製造方法
WO2000055145A1 (fr) Derives de 1,3,4-oxadiazole et leur procede de fabrication

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10835573

Country of ref document: EP

Kind code of ref document: A1

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10835573

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10835573

Country of ref document: EP

Kind code of ref document: A1