# Flow and Microwave Induced Pellizzari Reactions: Synthesis of Heterocyclic Analogues of the Benzoxazepine Antipsychotic Agents Loxapine and JL-13

Authors: Nadeesha Ranasinghe; Enrico Mongeau; Gengyang Yuan; Zachary Minden; Scott Waldron; Christopher Patrick; Farid Fouad; Sabiha Kappera; Graham B. Jones
Journal: Advances in Chemistry
 (2017)

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## Abstract

An expeditious route to fused triazolo-pyrido benzoxazepines has been developed using flow and microwave-mediated cyclization chemistry. A range of substituted aryl hydrazides are coupled with a core chloroimine in good to excellent yield via a Pellizzari type process, producing 1,2,4-triazolo-pyrido [2,3-b] [1,5] benzoxazepines with structural similarity to known antipsychotic agents. Modifications allow for strategically functionalized derivatives, and installation of a fluoro group for use in PET imaging is also demonstrated. Given the affinity of the tricyclic core for 5-HT and dopamine receptors, the derivatives are expected to find utility in CNS research.


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## Body

## 1. Introduction

Heterocyclic derivatives of the benzodiazepine and benzoxazepine class are of considerable interest in medicinal chemistry due to their pharmacologic and metabolic profiles [1, 2]. Prominent examples include the anxiolytic Alprazolam (Xanax®), Loxapine, and the atypical antipsychotic JL13, which has been investigated as a next-generation clozapine analogue [3–5]. One of the pharmacologic targets of the agents is the 5-HT2a receptor, and a number of heterocyclic analogues demonstrate high affinity including Asenapine which despite its altered geometry compares favorably to traditional agents Loxapine and Clozapine [6] (see Scheme 1). Given promising preclinical data reported for JL13 [7–9], we elected to study the potential of additional heterocyclic variants which might be readily accessible using efficient coupling strategies and which also highlights the benefits of green chemistry approaches [10, 11]. Given the functional flexibility of the triazole group and its presence in a number of pharmacologically active molecules [12], we sought to investigate use of the Pellizzari method [13], which relies on one pot coupling, and closure of imino chlorides with substituted hydrazides.Scheme 1


## 2. Results and Discussion

For initial studies we designed a series of hybrid triazole-benzoxazepine mimics of Loxapine and JL13, investigating the benefit of microwave and flow-mediated Pellizzari reactions as green approaches to these classes. A chloropyridyl amide substrate1 was firstly prepared by condensation of 2-chloro nicotinoyl chloride with 2-amino phenol (DIPEA, 94%). This was subjected to microwave accelerated base-mediated intramolecular closure to form2 (Scheme 2) with KOtBu (90%) preferable to both NaOH (72%) and NaH (59%) with a 5 min irradiation. The cyclic amide was converted to the corresponding chloroimine, allowing us to probe the key triazole forming reaction to produce3 (All new compounds were fully characterized by appropriate spectroscopic and analytical techniques.). A range of aryl hydrazide substrates were probed under thermal, microwave, and flow conditions at 100 mg scale and the results are summarized in Table 1.Table 1
Intramolecular cyclization to form triazolo benzoxepines3 (% isolated yield).
Entry
3
Ar
T
h
e
r
m
a
l
a
M
W
b
F
l
o
w
c
1
3a
Ph
38
54
57
2
3b
2-Cl-C6H4
48
86
78
3
3c
4-Cl-C6H4
66
96
84
4
3d
2-OH-C6H4
29
89
>99
5
3e
4-OH-C6H4
41
67
72
6
3f
3-OMe-C6H4
28
92
82
7
3g
3-pyridyl
57
84
98
8
3h
2-F-C6H4
25
88
>99
9
3i
3-F-C6H4
32
83
85
10
3j
4-Me-C6H4
39
98
88
11
3k
3-NO2-C6H4
17
81
85
12
3l
3-Cl-C6H4
44
80
—
n
a-BuOH, Δ, 118°C, 6 h; 300b W, 200°C, n-BuOH 15 min. Bothc pumps of the reactor were set to flow at equal rates (2 μl/min) at 190°C with a solution of 5-chlorobenzo[b]pyrido[3,2-f][1,4]oxazepine (0.04 M) and hydrazide (0.04 M) in n-BuOH with residence time of 2.5 min. Experiments represent n>3.Scheme 2
MW and flow based synthesis of triazolo-pyrido-benzoxazepines.Though moderate conversion was observed within 6 h of conventional thermolysis, the MW methods allowed very high yields of product within 15 mins withn-butanol being the most effective solvent. Essentially comparable, flow-mediated reactions (conducted using a Chemtrix Labtrix S1 system equipped with T-mixer) in some cases produced even higher yields, a presumed consequence of improved mixing interactions [14].Given literature reports citing the importance of both basic amino functionality and a hydrophobic substituent (e.g., chloroaryl group) for optimal receptor binding [15, 16], a more elaborate substrate5 was also prepared from hydrazide4 (readily available fromm-chloro-o-toluic acid), leading to the target compound in 87% yield (see Scheme 3). Given the impressive results with the MW Pellizzari reaction, a second family of analogues were prepared which contain the chloroaryl functionality on the parent tricyclic ring system. Amide6 (prepared from 2-chloro nicotinoyl chloride and 2-amino-4-chloro phenol) was subjected to base induced oxepane formation and subsequent chlorination to give7 in good yield (Scheme 4). Microwave induced Pellizzari reactions were conducted with various hydrazides to give substituted analogues8.Scheme 3Scheme 4
Modification of core for MW Pellizzari route to chlorinated series.A range of decorated analogues9–16 were produced in good to excellent yield (see Scheme 6), which, coupled with those depicted in Table 1, will allow insightful structure-activity studies to be performed with binding assays against key receptors (5-HT2a, 5-HT2c, D1, D2, and D4.2 being of importance, with the 5-HT2a/D2 ratio especially significant) [17]. In a preliminary assay, compound5 showed a Ki of 16 μM against 5-HT2a, which bodes well for in depth assays [18]. Finally, and with a potential view to studying biodistribution of these ligands viain vivo imaging methods, proof of principal was demonstrated for installation of a fluoro group via nucleophilic displacement. Following extensive optimization of parameters (temp, time, and stoichiometry), nitroarene17 was subjected to MW induced fluorodenitration to give18 in good yield within 15 mins at 140°C using 2 equivalents of TBAF in DMSO (Scheme 5) [19]. Given the half-life of its γ emitting sister 18F isotope (~120 mins) this rapid transformation is compatible with late stage labeling for PET imaging.Scheme 5
MW induced fluorodenitration.Scheme 6


## 3. Conclusions

Both MW and flow based Pellizzari reactions were effective and efficient for the production of new classes of substituted triazolo-pyrido fused benzoxazepines. The route provides access to compounds which may be useful probes of the 5-HT and dopamine receptors, based on similarity to known antipsychotic agents. A specimen compound shows measurable affinity for one of the receptor subtypes and derivatization of the core via nucleophilic fluorination provides a means to utilize the class in PET imaging studies. A comprehensive screening of these agents will be reported in due course.



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*Source: 8147421-2017-12-04.xml*