- Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5-C6 Disconnection and CO2H-NH2 Equivalence
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A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale.
- Cini, Elena,Banfi, Luca,Barreca, Giuseppe,Carcone, Luca,Malpezzi, Luciana,Manetti, Fabrizio,Marras, Giovanni,Rasparini, Marcello,Riva, Renata,Roseblade, Stephen,Russo, Adele,Taddei, Maurizio,Vitale, Romina,Zanotti-Gerosa, Antonio
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p. 270 - 283
(2016/03/04)
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- A stereoselective catalytic nitroaldol reaction as the key step in a strategy for the synthesis of the renin inhibitor aliskiren
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Aliskiren is the first-in-class orally active direct renin inhibitor. It was approved in 2007 for the treatment of hypertension. We have designed a new strategy for the convergent synthesis of aliskiren that involves a catalytic stereoselective nitroaldol reaction as the key step. A new enantiopure nitroalkane (synthon A1), prepared in only three steps from a commercially available enantiopure 2-(arylmethyl)-3-methyl butanol derivative, was successfully used in a copper-catalysed Henry reaction to give a nitrolactone intermediate in which the correct configuration for the final product was established at all four stereocentres. Nitro-group reduction, Boc-protection of the resulting amine, aminolysis of the lactone with 3-amino-2,2-dimethylpropionamide, and finally Boc-deprotection led to the enantiopure renin inhibitor aliskiren.
- Rossi, Sergio,Benaglia, Maurizio,Porta, Riccardo,Cotarca, Livius,Maragni, Paolo,Verzini, Massimo
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p. 2531 - 2537
(2015/04/22)
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- PROCESS FOR PREPARING 8-ARYLOCTANOIC ACIDS
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The present invention relates to a process for preparing aliskiren and, more particularly, to an improved method for synthesizing a β-amino alcohol or a lactone analog thereof via the corresponding nitro derivatives of formula (Ia) or (Ib) these intermediates being used in the preparation of aliskiren.
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Page/Page column 30; 31; 32
(2015/02/02)
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- Conception and evolution of stereocontrolled strategies toward functionalized 8-aryloctanoic acids related to the total synthesis of aliskiren
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A detailed account is given describing the approaches used toward the total synthesis of aliskiren. In particular, ring-closing metathesis with the Hoveyda-Grubbs catalyst accelerates the formation of a 9-membered lactone from an (R)-ester. The diastereom
- Hanessian, Stephen,Chnard, Etienne,Guesn, Sbastien,Cusson, Jean-Philippe
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p. 9531 - 9545
(2015/02/19)
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- Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical
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The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h-1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid-liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90-95%) under closed-loop control despite process disturbances.
- Heider, Patrick L.,Born, Stephen C.,Basak, Soubir,Benyahia, Brahim,Lakerveld, Richard,Zhang, Haitao,Hogan, Rachael,Buchbinder, Louis,Wolfe, Aaron,Mascia, Salvatore,Evans, James M. B.,Jamison, Timothy F.,Jensen, Klavs F.
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p. 402 - 409
(2014/04/17)
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- PROCESS FOR THE PREPARATION OF ALISKIREN
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The present invention provides a novel process and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially renin inhibitors, such as Aliskiren, or a salt thereof, preferably Aliskiren hemifumarate.
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- METHOD FOR PREPARING ALISKIREN AND ITS INTERMEDIATES THEREOF
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A method for preparing Aliskiren and intermediate thereof, which comprises the following steps: reacting 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene with magnesium isopropyl chloride and n-BuLi to obtain the compound of formula XXII; reacting the product of methylsulfonylation of the compound of formula XIX with anhydrous LiBr to obtain the compound of formula XXI; obtaining the intermediate of Aliskiren shown as formula XV by reacting the compound of formula XXII with the compound of formula XXI in an ether as the solvent and in the presence of a catalyst containing iron; then reacting the compound of formula XV with the compound of formula VII to obtain the compound of formula XXIII, following removing R1 from the amino group and obtaining Aliskiren shown as formula I.
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- PROCESS FOR THE PREPARATION OF ALISKIREN
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The present invention provides a novel process and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially renin inhibitors, such as Aliskiren, or a salt thereof, preferably Aliskiren hemifumarate.
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- METHOD FOR PREPARING ALISKIREN AND INTERMEDIATE THEREOF
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A method for preparing Aliskiren and intermediate thereof, which comprises the following steps: reacting 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene with magnesium isopropyl chloride and n-BuLi to obtain the compound of formula XXII; reacting the product of methylsulfonylation of the compound of formula XIX with anhydrous LiBr to obtain the compound of formula XXI; obtaining the intermediate of Aliskiren shown as formula XV by reacting the compound of formula XXII with the compound of formula XXI in an ether as the solvent and in the presence of a catalyst containing iron; then reacting the compound of formula XV with the compound of formula VII to obtain the compound of formula XXIII, following removing R1 from the amino group and obtaining Aliskiren shown as formula I.
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- CHEMICAL PROCESS FOR OPENING RING COMPOUNDS
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It is described a process for the opening of lactone or lactam rings useful in the synthesis of pharmaceutically active compounds and the intermediates thereof, particularly Aliskiren. It has found that by selecting a type of solvent it is possible to obtain excellent yields and high optical and chemical purity of the isolated products.
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Page/Page column 11; 12
(2013/03/26)
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- Chemical process for opening ring compounds
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It is described a process for the opening of lactone or lactam rings useful in the synthesis of pharmaceutically active compounds and the intermediates thereof, particularly Aliskiren. It has found that by selecting a type of solvent it is possible to obtain excellent yields and high optical and chemical purity of the isolated products.
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Paragraph 0050; 0051; 0052; 0053
(2013/03/26)
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- End-to-end continuous manufacturing of pharmaceuticals: Integrated synthesis, purification, and final dosage formation
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A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system. Copyright
- Mascia, Salvatore,Heider, Patrick L.,Zhang, Haitao,Lakerveld, Richard,Benyahia, Brahim,Barton, Paul I.,Braatz, Richard D.,Cooney, Charles L.,Evans, James M. B.,Jamison, Timothy F.,Jensen, Klavs F.,Myerson, Allan S.,Trout, Bernhardt L.
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supporting information
p. 12359 - 12363
(2013/12/04)
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- PROCESS FOR PREPARING ALISKIREN AND ITS INTERMEDIATES
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The present application relates to a process for the preparation of aliskiren and its pharmaceutically acceptable salts. In particular, the present application relates to a process for the preparation of intermediates for aliskiren, and their conversion to aliskiren or its salts.
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- Process for the manufacture of enantiomerically pure aryloctanoic acids as aliskiren
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The present invention relates to a novel manufacturing process and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially rennin inhibitors such as Aliskiren. The invention describes a preparation of enantiomerically pure 8-aryloctanoic acids of general formula I from readily available key intermediate, a novel bicyclic compound of formula IV.
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- Process for enantiomerically pure 8-Aryloctanoic acids as Aliskiren
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The present invention relates to a novel manufacturing process and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially rennin inhibitors such as Aliskiren. The invention describes a preparation of enantiomerically pure 8-aryloctanoic acids of general formula I from readily available key intermediate, chiral cis-diacid of formula II, aziridine of formula XI and a monocyclic compound of formula III.
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- Manufacturing process for enantiomerically pure 8-Aryloctanoic acids as Aliskiren
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The invention describes a novel technical process and novel intermediates useful for the manufacture of enantiomerically pure 8-aryloctanoic acids of the formula I which are pharmaceutically active compounds as rennin inhibitors.
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- Total synthesis of "Aliskiren": The first renin inhibitor in clinical practice for hypertension
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We report a "macrocycle route" toward aliskiren, a drug presently marketed for the treatment of hypertension, using a highly stereocontrolled approach starting from a common "isopropyl chiron". Highlights of the synthesis include a challenging RCM reaction to produce a nine-membered unsaturated lactone, a highly stereoselective catalytic Du Bois aziridination, and a regio- and diastereoselective aziridine ring-opening to a vicinal amino alcohol.
- Hanessian, Stephen,Guesne, Sebastien,Chenard, Etienne
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supporting information; experimental part
p. 1816 - 1819
(2010/09/16)
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- Amide bond formation via reversible, carboxylic acid-promoted lactone aminolysis
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A rapid carboxylic acid-promoted lactone aminolysis is reported. A number of carboxylic acids were found to promote this amide bond-forming transformation, with aliphatic acids being the most efficient. This reaction is an equilibrium process (Keq/s
- Foley, Megan A.,Jamison, Timothy F.
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supporting information; experimental part
p. 1177 - 1181
(2011/04/16)
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- SYTHESIS OF RENIN INHIBITORS INVOLVING A CYCLOADDITION REACTION
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The invention related to a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially renin inhibitors, such as Aliskiren. Inter alia, the invention relates to a process for the manufacture of a compound of the formula (III), wherein R, R1, and R' are as defined in the specification, or a salt thereof, and a compound of formula (IV) wherein R, R1, R2 and R' are as defined in the specification, and processes of manufacturing these.
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Page/Page column 58
(2010/11/26)
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- Structural modification of the P2′ position of 2,7-dialkyl- substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: The discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets
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Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades
- Maibaum, Jürgen,Stutz, Stefan,G?schke, Richard,Rigollier, Pascal,Yamaguchi, Yasuchika,Cumin, Frédéric,Rahuel, Joseph,Baum, Hans-Peter,Cohen, Nissim-Claude,Schnell, Christian R.,Fuhrer, Walter,Gruetter, Markus G.,Schilling, Walter,Wood, Jeanette M.
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p. 4832 - 4844
(2008/03/12)
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- ALTERNATIVE SYNTHESIS OF RENIN INHIBITORS AND INTERMEDIATES THEREOF
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The present invention relates to synthetic routes to prepare a compound of the formula (A); wherein R1 is halogen, C1-6 halogenalkyl, C1-6 alkoxy-C1-6 alcoxy or C1-6alkoxy-C1-6alkyl; R2 is halogen, C1-4alkyl or C1-4alkoxy; R3 and R4 are independently branched C3-6alkyl; and R5 is cycloalkyl, C1-6alkyl, C1-6hydroxyalkyl, Cl-6alkoxy-C 1-6alkyl, C1-6alkanoyloxy-C1-6alkyl, C1-6aminoalkyl, C1-6alkylamino-C 1-6alkyl, Cl-6dialkylamino-C1-6alkyl, C1-6alkanoylamino- C1-6alkyl, HO(O)C-Cl-6alkyl, C1-6alkyl-O-(O)C-C1-6alkyl, H2N-C(O)-Cl-6alkyl, C1-6alkyl-HN-C(O)-C1-6alkyl or (C1-6alkyl)2N-C(O)-C1-6alkyl; or a pharmaceutically acceptable salt thereof as well as key intermediates obtained when following these routes as well as their preparation.
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Page/Page column 48
(2010/10/20)
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- Practical synthesis of an orally active renin inhibitor aliskiren
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A convergent synthesis of aliskiren was accomplished via the use of Segment AB as the key intermediate, which was prepared via the coupling of the Grignard reagent derived from Segment B with Segment A, followed by subsequent oxidative lactonization.
- Dong, Hua,Zhang, Zhi-Liu,Huang, Jia-Hui,Ma, Rujian,Chen, Shu-Hui,Li, Ge
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p. 6337 - 6340
(2007/10/03)
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- METHODS OF TREATING ALZHEIMER'S DISEASE USING ARYL ALKANOIC ACID AMIDES
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Disclosed are methods for treating Alzheimer’s disease, and other diseases, and/or inhibiting beta-secretase enzyme, and/or inhibiting deposition of A beta peptide in a mammal, by use of compounds of formula 1 (1) wherein the variables R1-R8 and X are defined herein.
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