- 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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- Removal of heavy metals from organic reaction mixtures: Preparation and application of functionalized resins
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Using a toolbox, sulfur and amine ligands are attached to a variety of hydrophobic and hydrophilic resins, and the combinations were tested for the removal of heavy metals from a number of products, prepared by metal-catalyzed reactions. As a result, cheap combinations of silica resins and simple polyamines proved to be among the most effective metal scavengers particularly in apolar solvents such as cyclohexane. Expensive cyclic polyamines are not suitable, owing to kinetic retardation of complexation. Functionalized PEGbased polymers, originally designed for solid phase synthesis, show promising performance as metal scavengers. The results are discussed and compared to alternative approaches for purification such as salt-formation and chemical downstream transformation.
- Barbaras, Damien,Brozio, Joerg,Johannsen, Ib,Allmendinger, Thomas
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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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- Preparation method of aliskiren
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The invention discloses a preparation method of aliskiren. Aliskiren is prepared from (R)-t-butylsulfenamide and a compound VIII. The chiral induction effect of the (R)-t-butylsulfenamide is used to construct a required second chiral center and solve the problem of column chromatographic separation needed in the construction of a second chiral center, a third chiral center and a fourth chiral center. The preparation method of aliskiren has the advantages of simple operation, high yield, low cost, high device utilization rate, and suitableness for industrial production.
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- 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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- 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 32; 33
(2015/02/02)
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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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- 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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- PROCESS FOR THE PREPARATION OF ALISKIREN
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The present invention relates to an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts comprising reducing the compound of Formula-Z in presence of catalyst and ammonia. The present invention further relates to Aliskiren hemifumarate having diastereomeric impurity less than 0.2%.(F) H3C CH3 NH2 H3C 0 H3C CH3 Formula-Z
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Page/Page column 11
(2013/10/21)
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- ALISKIREN INTERMEDIATES AND A PROCESS FOR ANALYZING THE PURITY OF ALISKIREN
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The present invention provides aliskiren intermediates and impurities, and processes for preparation thereof. The present invention also provides processes for preparing aliskiren using these intermediates and impurities. These impurities can also be used as reference markers or reference standards in the determination of the purity of aliskiren or intermediates of aliskiren.
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Page/Page column 22
(2012/03/27)
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- A total synthesis of aliskiren
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A total synthesis of aliskiren (20) was accomplished. A key in our synthesis was to use the symmetric trans-cisoid-trans-bis-lactone 1 as a precursor. It was expediently prepared by three different routes (Scheme 2). Appending the end groups and functional group transformations completed the synthesis (Scheme 3). Copyright
- Nam, Gyeok,Ko, Soo Y.
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p. 1937 - 1945,9
(2012/12/12)
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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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- A new synthesis of the orally active renin inhibitor aliskiren
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A convergent synthesis of the orally active renin inhibitor aliskiren (1) is described. The synthesis was accomplished in 12 steps starting from the known chloride 2. The key step involves the Curtius rearrangement of the advanced intermediate 15, which provides lactone/carbamate 17 containing the correct stereochemistry and all of the functionality required for the preparation of the drug substance.
- Slade, Joel,Liu, Hui,Prashad, Mahavir,Prasad, Kapa
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p. 4349 - 4352
(2011/08/22)
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- THE RING OPENING OF LACTONES AND LACTAMS
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The present invention provides a novel process for opening a lactone and/or a lactam ring. More particularly, the present invention provides a process that employs a novel catalyst in the opening of a lactone ring and/or a lactam ring. Additionally, the present invention also provides a novel deprotection process of any protecting group present in either the lactone ring-containing and/or lactam ring-containing compound and/or in the ring-opened product thereof.
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Page/Page column 69-71
(2011/02/24)
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- PROCESS FOR THE PREPARATION OF (2S,4S,5S,7S)-N-(2-CARBAMYL-2- METHYLPROPYL)-5-AMINO-4-HYDROXY-2,7-DIISOPROPYL-8-[4-METHOXY-3-(3- METHOXYPROPOXY)PHENYL]-OCTANAMIDE HEMIFUMARATE AND ITS INTERMEDIATES THEREOF
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The present invention relates to a process for the preparation of (2S,4S,5S,7S)-N-(2- Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxy propoxy )phenyl]-octanamide compound of formula- 1 and its pharmaceutically acceptable salts thereof. Further, relates to the processes for the preparation of (R)-4-(2-(halomethyl)-3- methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene and (R)-2-(4-methoxy-3-(3-methoxy propoxy) benzyl)-3-methyIbutan-l-ol useful intermediates in the synthesis of compound of formula- 1.
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Page/Page column 54
(2011/12/14)
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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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Page/Page column 11
(2011/06/24)
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- A NOVEL PROCESS FOR MAKING ALISKIREN, ITS NOVEL INTERMEDIATES AND CERTAIN NOVEL COMPOUNDS
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A novel process for making Renin inhibitors like Aliskiren is disclosed. Its novel intermediate compounds and method of making them are also disclosed.
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Page/Page column 41-42
(2011/06/23)
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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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- 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 and intermediates for the preparation of aliskiren
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The present invention relates to a process and intermediates for the manufacture of aliskiren or pharmaceutically acceptable salts thereof.
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Page/Page column 28
(2010/06/15)
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- AMIDE INHIBITORS OF RENIN
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The present invention relates to new amide inhibitors of renin, pharmaceutical compositions thereof, and methods of use thereof
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- SYNTHESIS ROUTES TO 2(S),4(S),5(S),7(S)-2,7-DIALKYL-4-HYDROXY-5-AMINO-8-ARYL-OCTANOYL AMIDES
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The invention relates to a process for the preparation of compounds that are important building blocks in convergent synthesis routes to 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides or pharmaceutically acceptable salts thereof, such as the compound Aliskiren, and to a process for the preparation of these octanoyl amides, comprising reacting said building block.
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Page/Page column 49
(2010/04/03)
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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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- SOLID STATES OF ALISKIREN FREE BASE
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The present invention describes a solid state of aliskiren free base, and process for the preparation thereof.
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Page/Page column 7
(2009/12/28)
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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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- ORGANIC COMPOUNDS
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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, R2, R3 and PG are as defined in the specification, or a salt thereof, said manufacture comprising (preferably consisting in) reacting a Compound of the formula I, (I) with a reagent able to transform hydroxy into X where X is for example a leaving group.
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Page/Page column 42-43
(2008/06/13)
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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 47
(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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- Process for the preparation of aryloctanoyl amides
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Compounds of formula IwhereinR1is for example 3-methoxyprop-3-yloxy, R2is for example methoxy, R3and R4are in each case for example isopropyl, and R5is H2NC(O)-[C(CH3)2]-CH2-, are obtainable by reaction of compounds of formula IV(IV) with a metal organic derivative of 1-(3-R1-4-R2-phen-1-yl)-2-R3-3-halogen propanes to form a compound of formula VI,followed by removal of the pseudoephedrine protecting group and the OH group, reaction of the resulting lactone with an amine R5-NH2and removal of protecting group Z.
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- A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate
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We report a convergent synthesis of the potent orally active non-peptide renin inhibitor CGP60536B. The key reaction employs the coupling of the enantiopure Grignard species derived from chloride 13 with the diastereomerically pure γlactone 9b. The stereoselective reduction of the resulting ketone 14b has been thoroughly investigated. (C) 2000 Elsevier Science Ltd.
- Rueger,Stutz,Goschke,Spindler,Maibaum
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p. 10085 - 10089
(2007/10/03)
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