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several target compounds. The acetal group of the desired regio-
isomer was deprotected using aqueous hydrochloric acid to pro-
vide the aldehyde.
N
O
N
MeO2C
R1
CHO
Indazole rings with 5-methyl and 5-methoxy substituents were
accessed by using a diazotization approach (Scheme 3). Treatment
of methyl 2-amino-5-bromo-3-methylbenzoate with isoamyl ni-
trite and potassium acetate provided the indazole nucleus in good
yield. The product was subsequently alkylated with 2-bromo-1,1-
dimethoxyethane to provide bromide 7a following separation of
the regioisomers. The methyl group was installed using trim-
ethylboroxine under palladium catalysis to provide aldehyde 7b
following acetal removal. The 5-methoxy substituent of aldehyde
8b was prepared following a three-step sequence with the key
transformation involving the oxidative hydroxylation of an inter-
mediary pinacol boronate ester.
a-c
N
Y
N
Y
X
X
R1
1-3: X= CH, Y = CR2
4-8: X = N, Y = CH
9: X = CO, Y = NH
10: X = SO2, Y = NH
1b - 10b
Scheme 1. Diazepinone series. Reagents and conditions: (a) (i) (R)- or (S)-3-amino-
quinuclidineÁ2HCl, NaOMe, MeOH or NaH, CH2Cl2 or dioxane; (ii) 1% HOAc, (iii)
NaBH3CN or NaBH(OAc)3; (b) LiOH, 1:1 THF/H2O, heat; (c) T3P, DIPEA, THF. Three-
step yields: 18–65%.
To address the limitations of the N1 alkylation approach used
for the indazole scaffold in Scheme 2, a regio-controlled synthesis
was developed for indazole aldehyde 4b (Scheme 4). Bromination
of methyl 2-fluoro-3-methylbenzoate followed by DMSO oxidation
of the benzylic bromide gave intermediate aldehyde 4a. Compound
4a was treated with 2-hydrazinylethanol at room temperature in
methanol for 1 hour to promote hydrazone formation. The solution
of the putative hydrazone was subsequently heated in a micro-
wave to efficiently close the ring. Complex mixtures resulted if
the room temperature condensation step was omitted, presumably
due in part to competing SNAr displacement of the doubly acti-
vated aryl fluoride. Aldehyde 4b was obtained after Swern oxida-
tion of the intermediate alcohol.
Aldehyde 9b was accessed in a four step sequence (Scheme 5). A
high yielding displacement of the chloride was effected by treat-
ment of methyl 2-chloro-3-nitrobenzoate with 2,2-dimethoxye-
thanamine and triethylamine in THF under reflux. The nitro
group was subsequently reduced with hydrogen and palladium
on carbon to provide diamine 9a. The benzimidazolidinone ring
was achieved by treatment of 9a with carbonyl diimidazole. Alde-
hyde 9b was then generated by deprotection of the acetal protect-
ing group with wet TFA in methylene chloride.
Aldehyde 10b was prepared from common intermediate 9a
(Scheme 5). Diamine 9a was treated with sulfuric diamide in
refluxing diglyme to give the sulfonamide heterocycle. The acetal
was deprotected with TFA in water to provide aldehyde 10b.
The new diazepinone series are potent h5-HT3A receptor inhib-
itors. Ki values for 3, 6, 7 are comparable to alosetron (Table 1).14
There is an affinity preference for (S)-enantiomer (compare 1 and
2). Four heterocyclic ring systems were explored (e.g., indole, inda-
zole, imidazolidinone and 1,3-dihydrobenzo[c][1,2,5]thiadiazole
2,2-dioxide). Single digit nanomolar Ki values were observed for
the unsubstituted parent compounds (2, 4 and 9) excepting sulfon-
amide 10. For optimization efforts, the flexibility to use different
heterocyclic cores was attractive, in part, because the in vitro ago-
nist responses as measured using HEK293 cells heterologously
expressing the h5-HT3A receptor covered a wide range of starting
intrinsic activities for these same compounds.14
with increased heterocyclic diversity and lead to a better under-
standing of the range of partial agonism at the 5-HT3 receptor that
could be derived from such compounds for a potential therapeutic
agent.9
To prepare these compounds, we adopted a synthetic strategy
to introduce the quinuclidine bicyclic amine late in the synthetic
sequence using a general three step sequence. Principally, this ap-
proach overcomes several practical complications using the polar,
highly nucleophilic quinuclidine at an early stage. Quinuclidine’s
unusual properties can dominate a chemical route. For example,
the quinuclidine tertiary nitrogen is ꢀ104 times more nucleophilic
than triethylamine.10 It can therefore preferentially undergo facile
alkylation chemistry, even with CH2Cl2, which confounds the use
of common normal phase flash chromatography eluents ordinarily
effective for amine-bearing compounds (e.g., CH2Cl2/MeOH mix-
tures). Quinuclidine-bearing intermediates can adversely affect
the efficiency of aqueous work-up strategies due to generally good
water solubility or by their polar nature. Collectively, these consid-
erations led us to introduce the quinuclidine moiety as late as fea-
sible in the synthesis.
Accordingly, enantiomerically pure (R)- or (S)-3-aminoquinucli-
dine dihydrochloride, which can be readily purchased, was coupled
with the requisite aldehyde using reductive amination conditions
(Scheme 1).11 It was important to first free base the amine hydro-
chloride salt. The seven-membered diazepinone ring was then gen-
erated by first unmasking the carboxylic acid through basic
saponification of the ester followed by subsequent lactamization,
usually with propylphosphonic anhydride (T3PÒ).12 This sequence
led to the synthesis of compounds 1–10 which encompass four
heterocyclic scaffolds.
The aldehydes (1b–10b) necessary to prepare the corresponding
target diazepinones (1–10) were prepared by several methods
(Schemes 2–5). Methyl 1H-indole-7-carboxylate,13 methyl 5-chlor
o-3-methyl-1H-indole-7-carboxylate,14 methyl 5-fluoro-1H-inda-
zole-7-carboxylate,14 and methyl 5-chloro-1H-indazole-7-carboxyl-
ate,14 were alkylated with 2-bromo-1,1-dimethoxyethane by
in situ conversion of the bromide to the iodide (Scheme 2).
For indazole rings (X = N), the major product from the alkyl-
ation was the undesired N2 alkylated isomer. Despite this draw-
back, the shortness of the route enabled the rapid synthesis of
OMe
MeO2C
MeO2C
MeO2C
CHO
OMe
NH2
a,b
N
7b: c, g
8b: d-g
N
N
N
MeO2C
MeO2C
R1
CHO
1b: X = CH, R1, R2 = H
H
N
Br
Br
R1
3b: X = CH, R1 = Cl, R2 = Me
5b: X = N, R1 = F, R2 = H
6b: X = N, R1 = Cl, R2 = H
N
a,b
7a
7b: R1 = Me
8b: R1 = OMe
X
X
R1
R2
R2
Scheme 3. Synthesis of aldehyde 7b and 8b. Reagents and conditions: (a) (i) Ac2O,
CHCl3; (ii) KOAc, isoamyl nitrite, reflux, 88%; (b) KI, 2-bromo-1,1-dimethoxyethane,
DBU, DMSO, 80 °C, 20%; (c) Pd(PPh3)4, K2CO3, trimethylboroxine, 100 °C, 51%; (d)
KOAc, bis(pinacolato)diboron, Pd(dppf)Cl2ÁCH2Cl2, DMSO, 80 °C, 50%; (e) 30% H2O2,
MeOH, 85%; (f) Cs2CO3, MeI, DMF, 96%; (g) 2 N HCl, dioxane, 75 °C.
Scheme 2. Synthesis of aldehydes 1b, 3b, 5b and 6b. Reagents and conditions: (a)
1b and 3b: NaH, KI, 2-bromo-1,1-dimethoxyethane, DMF, 80 °C, 59–68% or for 5b,
6b: DBU, KI, 2-bromo-1,1-dimethoxyethane, DMSO, 80 °C, 11–15%; (b) 1–2 N HCl,
THF, 60 °C, 2 h, 76–89%.