1. Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders
Peng Li, Qiang Zhang, Albert J Robichaud, Taekyu Lee, John Tomesch, Wei Yao, J David Beard, Gretchen L Snyder, Hongwen Zhu, Youyi Peng, Joseph P Hendrick, Kimberly E Vanover, Robert E Davis, Sharon Mates, Lawrence P Wennogle Multicenter StudyJ Med Chem. 2014 Mar 27;57(6):2670-82.doi: 10.1021/jm401958n.Epub 2014 Mar 5.
We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.
2. An Improved Scalable Synthesis of the Potent Antiviral (S)-HPMPA
Racherla Kishore Kumar, Yogesh S Sanghvi, Paidi Yella Reddy, Shyamapada Banerjee Curr Protoc. 2022 Nov;2(11):e602.doi: 10.1002/cpz1.602.
We present an improved synthesis of (S)-HPMPA (1) from an easily accessible and commercially available compound, (S)-3-(benzyloxy)propane-1,2-diol (10). Tritylation of primary alcohol 10 was highly selective, and pure product was isolated in good yield. Alkylation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) with diethyl p-toluenesulfonyloxymethyl phosphonate (6) using sodium hydride in tetrahydrofuran followed by detritylation afforded the desired chiral synthon 12. Tosylation of the primary alcohol and subsequent reaction with sodium adeninate afforded protected S-HPMPA (14). Global deprotection using concentrated hydrochloric acid in a sealed tube afforded S-HPMA (1), and the deprotected 1 was crystallized from water and acetone to obtain a 99% pure product. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) Basic Protocol 2: Preparation of diethyl (S)-(((1-(benzyloxy)-3-hydroxypropan-2-yl)oxy)methyl)phosphonate (12) Basic Protocol 3: Preparation of (R)-3-(benzyloxy)-2-((diethoxyphosphoryl)methoxy)propyl-4-methylbenzenesulfonate (13) Basic Protocol 4: Preparation of diethyl (S)-(((1-(6-amino-9H-purin-9-yl)-3-(benzyloxy)propan-2-yl)oxy)methyl)phosphonate (14) Support Protocol 1: Preparation of sodium adeninate Basic Protocol 5: Preparation of (S)-(((1-(6-amino-9H-purin-9-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonic acid (1).
3. 2-Ammonio-5-chloro-4-methylbenzenesulfonate, its 1-methyl-2-pyrrolidone and dimethyl sulfoxide monosolvates and a corrected structure of 2,2'-(1,4-phenylene)di(4,5-dihydroimidazolium) bis(4-aminobenzenesulfonate) dihydrate
Sándor L Bekö, Jan W Bats, Martin U Schmidt Acta Crystallogr C. 2012 Feb;68(Pt 2):o45-50.doi: 10.1107/S0108270111054205.Epub 2012 Jan 6.
2-Ammonio-5-chloro-4-methylbenzenesulfonate, C(7)H(8)ClNO(3)S, (Ia), is an intermediate in the synthesis of lake red azo pigments. The present structure determination from single-crystal data confirms the results of a previous powder diffraction determination [Bekö, Thoms, Brüning, Alig, van de Streek, Lakatos, Glaubitz & Schmidt (2010). Z. Kristallogr. 225, 382-387]. The zwitterionic tautomeric form is confirmed. During a polymorph screening, two additional pseudopolymorphs were obtained, viz. 2-ammonio-5-chloro-4-methylbenzenesulfonate 1-methyl-2-pyrrolidone monosolvate, C(7)H(8)ClNO(3)S·C(5)H(9)NO, (Ib), and 2-ammonio-5-chloro-4-methylbenzenesulfonate dimethyl sulfoxide monosolvate, C(7)H(8)ClNO(3)S·C(2)H(6)OS, (Ic). The molecules of (Ib) have crystallographic m symmetry. The 1-methyl-2-pyrrolidone solvent molecule has an envelope conformation and is disordered around the mirror plane. The structure shows hydrogen-bonded ladders of molecules [graph-set notation C(2)(2)(6)R(2)(2)(12)] in the [010] direction. The benzene groups of adjacent ladders are also stacked in this direction. A different type of hydrogen-bonded ladder [graph-set notation C(6)R(2)(2)(4)R(4)(4)(12)] occurs in (Ic). In (Ia), (Ib) and (Ic), the molecules correspond to the zwitterionic tautomer. The structure of the cocrystal of 4-aminobenzenesulfonic acid with 1,4-bis(4,5-dihydroimidazol-2-yl)benzene [Shang, Ren, Wang, Lu & Yang (2009). Acta Cryst. E65, o2221-o2222] is corrected; it actually contains 4-aminobenzenesulfonate anions and 2,2'-(1,4-phenylene)di(dihydroimidazolium) dications, i.e. 2,2'-(1,4-phenylene)di(4,5-dihydroimidazolium) bis(4-aminobenzenesulfonate) dihydrate, C(12)H(16)N(4)(2+)·2C(6)H(6)NO(3)S(-)·2H(2)O. Hence, all known structures of aminobenzenesulfonic acid complexes contain ionic or zwitterionic molecules; there is no known structure with a neutral aminobenzenesulfonic acid molecule.
