- 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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- AN IMPROVED PROCESS FOR THE PREPARATION OF ALISKIREN
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The present invention relates to an improved process for the preparation of renin inhibitor Aliskiren intermediates of Formula-II and further conversion into Aliskiren and its pharmaceutically acceptable salts.
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- An improved and economical process for the manufacture of the key intermediate of aliskiren, a new potent renin inhibitor
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An improved, practical, economical and efficient process for the production of (2S,4S)-2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoic acid, a key intermediate of the new potent renin inhibitor of aliskiren, in a total yield over 30% is described. This process avoids expensive reagents and chromatographic purifications, and is easily scaled up in industry.
- Wang, Fan,Xu, Xiao-Ying,Wang, Fei-Ying,Peng, Lin,Zhang, Yong,Tian, Fang,Wang, Li-Xin
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p. 1458 - 1462
(2013/12/04)
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- Acid promoted CIDT for the deracemization of dihydrocinnamic aldehydes with Betti's base
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Racemic α-epimerizable and unfunctionalized aldehydes have been converted into enantiomerically enriched mixtures through a sequence of (i) a conversion into the diastereoisomeric 3-substituted 1-phenyl-2,3-dihydro-1H- naphtho[1,2-e][1,3]oxazines by reaction with the (R)- or (S)-1-(α- aminobenzyl)-2-naphthol (Betti's base), (ii) an acid promoted crystallization-induced diastereoisomer transformation (CIDT), and (iii) a clean cleavage of the dihydro-1,3-naphthoxazinic ring of the enriched diastereoisomer, easily collected by filtration, allowing the recovery of the enantiomerically enriched aldehydes and the chiral auxiliary.
- Rosini, Goffredo,Paolucci, Claudio,Boschi, Francesca,Marotta, Emanuela,Righi, Paolo,Tozzi, Francesco
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scheme or table
p. 1747 - 1757
(2011/02/28)
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- 1-HETEROCYCLYLAMINO-2-HYDROXY-3-AMINO-ω-ARYLALKANES
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1-Heterocyclylamino-2-hydroxy-3-amino-?-arylalkanes of formula (I) and the salts thereof have renin-inhibiting properties and can be used as antihypertensive, medicinally active ingredients.
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- 1-ACYLAMINO-2-HYDROXY-3-AMINO-W-ARYLALKANES AS RENIN INHIBITORS
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1-Acylamino-2-hydroxy-3-amino-ω-arylalkanes of formula I. and the salts thereof, have renin-inhibiting properties and can be used as antihypertensive, medicinally active ingredients.
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Page/Page column 73; 75
(2008/06/13)
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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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- The nonchiral bislactim diethoxy ether as a highly stereo-inducing synthon for sterically hindered, γ-branched α-amino acids: A practical, large-scale route to an intermediate of the novel renin inhibitor aliskiren
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The diastereoselective synthesis of the sterically hindered, γ-branched α-amino acid derivative (2S,4S)-24a and its N-[(tert-butoxy)carbonyl](Boc)-protected alcohol (2S,4S)-19, both key intermediates of a novel class of nonpeptide renin inhibitors such as aliskiren (1), is described. Initially, the analogous methyl ester (2S,4S)-17 was obtained by alkylation of the chiral Schoellkopf dihydropyrazine (R)-12a with the dialkoxy-substituted alkyl bromide (R)-11a, which proceeded with explicitly high diastereofacial selectivity (ds > 98%) to give (2S,SR,2′S)-13a (Scheme 4), followed by mild acid hydrolysis and N-Boc protection (Scheme 5). Conversely, the complete lack of stereocontrol and poor yields for the reaction of (R)-11a with the enantiomeric (S)-12b suggested, in addition to the anticipated shielding effect by the iPr group at C(2) of the auxiliary, steric repulsion between the MeO-C(6) and the bulky residues of (R)-11a in the proposed transition state, which would strongly disfavor both the Si and Re attack of the electrophile (see Fig.). Based on this rationale, alkylation of the readily accessible achiral diethoxy-dihydropyrazine 21 with (R)-11a was found to provide a 95:5 mixture of diastereoisomers (2S,2′S)-22a and (2R,2′S)-23a in high yield (Scheme 6), which afforded in two steps and after recrystallization enantiomerically pure (2S,4S)-24a. Similarly, the stereochemical course for the alkylation reactions of the related alkyl bromides (S)-28a and (R)-28b with both (R)-12a and (S)-12b as well as with the achiral 21 was investigated (Schemes 7-9). The precursor bromides (R)-11a, (S)-11b, (R)-28a, and (S)-28b were efficiently synthesized via the diastereoselective alkylation of the Evans 3-isovaleroyloxazolidin-2-ones (R)-7a and (S)-7b either with bromide 6 or with benzyl chloromethyl ether, and subsequent standard transformations (Schemes 3 and 7). A practical and economical protocol of the preparation of (2S,4S)-24a on a multi-100-g scale is given. This is the first report of the application of an achiral dihydropyrazine, i.e., in form of 21, as a highly stereo-inducing synthon providing rapid access to a N-protected γ-branched α-amino acid with (2S) absolute configuration.
- Goeschke, Richard,Stutz, Stefan,Heinzelmann, Walter,Maibaum, Juergen
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p. 2848 - 2870
(2007/10/03)
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