82716-91-4Relevant academic research and scientific papers
Continuous Flow Synthesis of ACE Inhibitors From N-Substituted l-Alanine Derivatives
Breen, Christopher P.,Jamison, Timothy F.
supporting information, p. 14527 - 14531 (2019/11/03)
A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h?1, all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h?1.
PREPARATION OF QUINAPRIL HYDROCHLORIDE
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Page/Page column 5, (2008/06/13)
Methods and materials for preparing quinapril, its pharmaceutically acceptable salts, including quinapril hydrochloride, are disclosed. The method includes reacting (2S,4S)-2-(4-methyl-2,5-dioxo-oxazolidin-3-yl)-4-phenyl-butyric acid ethyl ester with (3S)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid tert-butyl ester to yield quinapril tert-butyl ester, which is subsequently reacted with an acid to yield quinapril or an acid addition salt of quinapril.
Concise, catalytic asymmetric synthesis of tetrahydroisoquinoline- and dihydroisoquinoline-3-carboxylic acid derivatives
Ooi,Takeuchi,Maruoka
, p. 1716 - 1718 (2007/10/03)
Catalytic asymmetric synthesis of tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives 1 has been accomplished by the successful utilization of phase-transfer catalysis of the C2-symmetric chiral quaternary ammonium bromides. Our approach also enables facile synthesis of quaternary isoquinoline derivatives 2 and 3 with high enantiomeric purities.
Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary δ opioid antagonist activity
Salvadori, Severe,Balboni, Gianfranco,Guerrini, Remo,Tomatis, Roberto,Bianchi, Clementina,Bryant, Sharon D.,Cooper, Peter S.,Lazarus, Lawrence H.
, p. 3100 - 3108 (2007/10/03)
The δ opioid antagonist H-Dmt-Tic-OH (2',6'-dimethyl-L-tyrosyl-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid) exhibits extraordinary δ receptor binding characteristics [K(i)(δ) = 0.022 nM; K(i)(μ)/K(i)(δ) = 150 000] and δ antagonism (pA2 = 8.2; Ke = 5.7 nM). A change in chirality of Dmt at Cα (1, 2, 6, 8, 10, 13) curtailed δ receptor parameters, while replacement of its α-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with δ receptors. N-Alkylation of H- Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent δ-opioid ligands with high δ receptor binding capabilities and enhanced δ antagonism: (i) N-Me-Dmt-Tic-OH 5 had high δ opioid binding (K(i)(δ) = 0.2 nM), elevated δ antagonism on mouse vas deferens (MVD) (pA2 = 8.5; K(e) = 2.8 nM), and nondetectable μ activity with guinea pig ileum (GPI). (ii) N,N- Me2-Dmt-Tic-OH (12) was equally efficacious in δ receptor binding (K(i)(δ) = 0.12 nM; K(i)(μ)/K(i)(δ) = 20 000), but δ antagonism rose considerably (pA2 = 9.4; K(e) = 0.28 nM) with weak μ antagonism (pA2 = 5.8; K(e) = 1.58 μM; GPI/MVD = 1:5640). N-Me-(9) and N,N-Me2-Dmt-Tic-Ala-OH (15) also augmented δ opioid receptor binding, such that 15 demonstrated high affinity (K(i)(δ) = 0.0755 nM) and selectivity (K(i)(μ)/K(i)(δ) = 20 132) with exceptional antagonist activity on MVD (pA2 = 9.6; K(e) = 0.22 nM) and weak antagonism on GPI (pA2 = 5.8; K(e) = 1.58 μM; GPI/MVD = 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high K(i)(δ) (0.31 nM) and excellent antagonist activity (pA2 = 9.9; K(e) = 0.12 nM), the increased activity toward μ receptors in the absence of a free acid function at the C- terminus revealed modest δ selectivity (K(i)(μ)/KK(i)(δ) = 1 655) and somewhat comparable bioactivity (GPI/MVD = 4500). Thus, the data demonstrate that N,N-(Me)2-Dmt-Tic-OH (12) and N,NMe2-Dmt-Tic-Ala-OH (15) retained high δ receptor affinities and δ selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non- peptide δ antagonists.
Studies on angiotensin-converting enzyme inhibitors. I. Syntheses and angiotensin-converting enzyme inhibitory activity of 2-(3-merecaptopropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives
Hayashi,Ozaki,Nunami,Uchida,Kato,Kinashi,Yoneda
, p. 570 - 576 (2007/10/02)
(3S)-2-[(2S)-mercapto-2-methylpropionyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [(3S), (2S)-6a] was prepared by the reaction of (3S)-1,2,3,4-tetrahydreoisoquinoline-3-carboxylic acid test-butyl ester [(3S)-2a) or benzyl ester [(3S)-2b] with 3-benzoylthio-2-methylpropionyl chloride (3a), followed by fractional crystallization and removal of the protective group. The absolute configuration of (3S), (2S)-6a was confirmed by X-ray diffraction analysis of the thiazepinol[4,3-b]isoquinoline compound (7) derived from 6a. Resolution of 3-benzoylthio-2-methylpropionic acid (8) was completed by using optically active phenylalanine amide as a resolving agent. The other optical isomers of (3S),(2S)-6a were prepared by the reaction of (3S)- or (3R)-2b with optically active 3a. The in vitro ACE inhibitory activity of each isomer of 6a was evaluated. Among them, (3S),(2S)-6a was found to be the most potent inhibitor with an IC50 value of 8.6X10-9M. Compound (3S),(2S)-6a induced a dose-dependent inhibition of the pressor response to angiotensin 1 after oral administration to normotensive anesthetized rats. Moreover, (3S),(2S)-6a markedly reduced the systolic blood pressure in renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR). The in vivo ACE inhibitory activity and the hypotensive effects of (3S),(2S)-6a were comparable to those of captopril.
