58402-40-7Relevant academic research and scientific papers
Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment
Bianchi, Barbara,Cai, Chunlong,Grand-Guillaume Perrenoud, Alexandre,Hardegger, Leo A.,Humair, Roger,Kaehny, Richard,Lanz, Stephan,Li, Cheng,Li, Jialiang,Mallet, Franck,Rampf, Florian,Shi, Lei,Spoendlin, Christoph,Staüble, Jeannine,Teng, Shangjun,Tian, Xiangguang,Wietfeld, Bernhard,Yang, Yao,Yu, Bo,Zepperitz, Christine,Zhang, Xuesong,Zhang, Yong
, p. 1743 - 1755 (2020/10/27)
We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet-Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet-Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.
Regioselective synthesis of phenanthrenes and evaluation of their anti-oxidant based anti-inflammatory potential
Kanekar, Yogesh,Basha, Khalander,Duche, Sharad,Gupte, Rajan,Kapat, Arnab
supporting information, p. 454 - 463 (2013/10/01)
Regioselective synthesis of 9,10-Dihydro-2,5-Dimethoxyphenanthrene-1,7-diol (1) and 9,10-Dihydro-2,7-Dimethoxyphenanthrene-1,5-diol (2) was achieved using regioselective methylation, Wittig reaction, intramolecular cyclization and hydrogenation as key ste
Two approaches to the aromatic core of the aminonaphthoquinone antibiotics
Nawrat, Christopher C.,Palmer, Leoni I.,Blake, Alexander J.,Moody, Christopher J.
, p. 5587 - 5603 (2013/07/26)
Two complementary approaches are presented for the synthesis of the quinone chromophores of the naphthoquinone ansamycins and related natural products. The first involves the use of an improved protocol for the manganese(III) acetate mediated cyclization of 5-aryl-1,3-dicarbonyl compounds to β-naphthols, leading to the simple, scalable preparation of building blocks suitable for the synthesis of naturally occurring aminonaphthoquinones. The second approach involves the Diels-Alder reaction of a series of new, ester-containing Danishefsky-type dienes with N-protected aminobenzoquinones to allow more expeditious access to similar intermediates.
Radical-mediated cyclisation of δ-aryl-β-dicarbonyl compounds to β-tetralones [3,4-dihydronaphthalen-2(1H)-ones]
Jamie, Joanne F.,Rickards, Rodney W.
, p. 2603 - 2613 (2007/10/03)
δ-Aryl-β-dicarbonyl compounds carrying electron-releasing groups in the aromatic ring undergo efficient radical-mediated oxidative cyclisation to β-tetralones in the presence of four equivalents of manganese(III) acetate in acetic acid. Secondary oxidation invariably results in acetoxylation at the benzylic α-position of the initially-formed β-tetralones. Use of the oxidant cerium(IV) ammonium nitrate in methanol affords the corresponding α-methoxylated β-tetralones. The α-acetoxy-α-acyl-β-tetralones, but not their α-acetoxy-α-alkoxycarbonyl analogues, are aromatised in high yield on treatment with alkaline silica gel, providing an effective synthetic entry to appropriately substituted β-naphthols. The possible involvement of such radical-mediated intramolecular annulations of δ-aryl β-diketone intermediates in the biosynthetic formation of the second carbocyclic ring of the naphthalenoid ansamycin antibiotics is discussed in relation to the previously proposed Michael addition mechanism.
DOPAMINERGIC COMPOUNDS
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, (2008/06/13)
Novel compounds of Formula (I): STR1 or pharmaceutically acceptable salts, esters and amides thereof, wherein A is O, C, CH or CH. sub.2, n is 0 or 1, and the dotted line is a single bond when A is O or CH 2 and a double bond when A is CH or when n=0, A is C and R 6 and A taken together form a nitrogen-containing heterocycle;R is hydrogen, lower alkyl or a readily cleavable group;R. sub.1 is selected from hydrogen, halogen, lower alkyl, haloalkyl and lower alkoxy;R 2 is selected from hydrogen, halogen, lower alkyl and haloalkyl or, taken together with R 8, forms a fused ring;R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or arylalkyl or, taken together with R 4, forms a spirocycloalkyl or, taken together with R 5, forms a fused cycloalkyl;R 4 is hydrogen or alkyl or, taken together with R 3, forms a spirocycloalkyl;R 5 is hydrogen or alkyl or, taken together with R 3, forms a fused cycloalkyl;R 6 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or arylalkyl or, taken together with A when A is C and when n is 0, forms a fused nitrogen-containing heterocycle or, taken together with R. sub.7 or R 8, forms a nitrogen-containing heterocycle;R. sub.7 is hydrogen or alkyl or, taken together with R 6 or R 8, forms a nitrogen-containing heterocycle;R 8 is hydrogen or alkyl or, taken together with R 6 or R 7, forms a nitrogen-containing heterocycle or, taken together with R 2, forms a fused ring, with the proviso that R 3 and R 4 cannot simultaneously both be hydrogen, are selective dopaminergic agents and are useful for treating disorders characterized by abnormal dopaminergic activity in the central or the peripheral nervous system, for example, neurological disorders such as psychoses, Parkinson's Disease, certain cardiovascular disorders and addictive behavior disorders.
Synthesis and Pharmacological Evaluation of 1-(Aminomethyl)-3,4-dihydro-5-hydroxy-1H2-benzopyrans as Dopamine D1 Selective Ligands
Michaelides, Michael R.,Schroenleber, Robert,Thomas, Sheela,Yamamoto, Diane M.,Britton, Donald R.,et al.
, p. 2946 - 2953 (2007/10/02)
A series of 3-substituted 1-(aminomethyl)-3,4-dihydro-5-hydroxy-1H-2-benzopyrans were prepared as potential D1 selective antagonists.The compounds were evaluated for their affinity and selectivity for D1 receptor as well as for their functional antagonism
