Concise and simple synthesis of M1 allosteric agonist TBPB

Article abstract of DOI:10.1080/00397911.2012.670740

A concise and simple synthesis of M₁ allosteric agonist 1-(1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d] imidazol-2(3H)-one (TBPB) using economical and commercially available orthophenylenediamine (O-PDA) and Boc piperidone has been described. The disclosed scheme allows synthesizing more analogs that were otherwise difficult to prepare with the original method. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.670740

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Concise and Simple Synthesis of M1
Allosteric Agonist TBPB
Mohammed Abdul Rasheed a , Nagul Meera Shaik a & Ramakrishna
Nirogi a
a Discovery Research, Medicinal Chemistry, Suven Life Sciences
Limited, Serene Chambers, Hyderabad, India
Accepted author version posted online: 27 Dec 2012.Version of
record first published: 04 Apr 2013.
To cite this article: Mohammed Abdul Rasheed , Nagul Meera Shaik & Ramakrishna Nirogi (2013):
Concise and Simple Synthesis of M1 Allosteric Agonist TBPB, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:13, 1796-1801
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Synthetic Communications1, 43: 1796–1801, 2013
Copyright # Suven Life Sciences Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.670740
CONCISE AND SIMPLE SYNTHESIS OF M1 ALLOSTERIC
AGONIST TBPB
Mohammed Abdul Rasheed, Nagul Meera Shaik, and
Ramakrishna Nirogi
Discovery Research, Medicinal Chemistry, Suven Life Sciences Limited,
Serene Chambers, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A concise and simple synthesis of M1 allosteric agonist 1-(10-(2-methylbenzyl)-
1,40-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (TBPB) using economical and
commercially available orthophenylenediamine (O-PDA) and Boc piperidone has been
described. The disclosed scheme allows synthesizing more analogs that were otherwise
difficult to prepare with the original method.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Boc-piperidone; EC50; microwave irradiation; NMR data; O-PDA; reductive
amination
INTRODUCTION
The muscarinic acetylcholine receptors (mAChRs) are members of superfamily A
of the G-protein- coupled receptors (GPCRs) and are activated by their native ligand
neurotransmitter acetylcholine (ACh)[1–4] in the peripheral and central nervous system
(CNS). Five muscarinic subtypes are known.[2–4] M1–M5 mAChRs are widely distrib-
uted in mammalian organs in the central and peripheral nervous system, where they
mediate important neuronal and autocrine functions including memory and attention
mechanisms, motor control, and nociception.[5,6] In particular, selective M1 agonism
has been suggested as a therapeutic approach in dementia including Alzheimer’s dis-
ease and age-related memory impairment associated with schizophrenia.[7] We were
Received December 29, 2011.
Address correspondence to Mohammed Abdul Rasheed, Discovery Research, Medicinal
Chemistry, Suven Life Sciences Limited, Serene Chambers, Road 5, Avenue 7, Banjara Hills,
Hyderabad 500 034, India. E-mail: rasheed@suven.com
1796

M1 ALLOSTERIC AGONIST TBPB
1797
Figure 1. The structure of TBPB, a selective M1 allosteric agonist.
interested in making some of the reported selective M1 allosteric agonists as reference
standards for our ongoing M1 program. 1-(10-(2-Methylbenzyl)-1,40-bipiperidin-4-yl)-
1H-benzo[d]imidazol-2(3H)-one (TBPB; 1, Fig. 1)[8] is one of the few selective M1 ago-
nists reported in the literature.[9] The TBPB 1 is a potent centrally active and highly
selective M1 allosteric agonist that displayed robust efficacy in several preclinical anti-
psychotic models and it has shown significant effects on the processing of amyloid pre-
cursor protein (APP) towards nonamyloidogenic pathway. It also decreased Ab
production.[10] However, TBPB 1 has an undesirable antagonist activity at D2 receptor
(IC50 ¼ 2.6 mM).[10,11] Our efforts at obtaining the potent M1 allosteric agonists sans
activity at D2 receptor will be reported elsewhere.
RESULTS AND DISCUSSION
The synthesis of TBPB (1) has been reported by Lindsley et al.[8] as depicted in
Scheme 1.
Scheme 1. Reagents and conditions: (a) Na2CO3, KI, cyclohexanol, mw, 180 ꢀC, 10 min, 70–90%; (b) Zn,
1 N HCl, MeOH; (c) triphosgene, Et3N, THF, rt, 2 h; (d) 10% NaOH, mw, 130 ꢀC, 30 min, 50–60% from 4;
and (e) MP-B(OAc)3H, CH2Cl2, 80%.

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M. A. RASHEED, N. M. SHAIK, AND R. NIROGI
Scheme 2. Reagents and conditions: (a) NaB(OAc)3H, AcOH, CH2Cl2, rt, 62%; (b) triphosgene, CH2Cl2,
NaHCO3, rt, 100%; (c) TFA, CH2Cl2, rt, 100%; and (d) NaB(OAc)3H, AcOH, CH2Cl2, rt, 78%.
The synthetic scheme involved five steps and two of the steps (i.e., the nucleo-
philic displacement of the fluoro group in the first step and the deprotection of ethyl-
carbamate in the fourth step) involved microwave-irradiation conditions. We felt it
would be convenient if we could avoid the microwave-irradiation conditions and
also other harsh conditions[9a] required to effect these transformations. Another rea-
son for establishing the current scheme is that the starting materials are economical
and commercially available. We envisaged a simple double reductive amination pro-
tocol starting with the economical and commercially available o-phenylenediamine
(O-PDA, 9) and Boc piperidone (10) as shown in Scheme 2.
The Boc piperidone (10), on subjecting to reductive amination reaction con-
ditions with O-PDA (9) in the presence of sodium triacetoxyborohydride, afforded
the desired mono-alkylated product (11) and undesired bis-alkylated compound
(12) in 62 and 21% yields respectively after a simple silica-gel column chromato-
graphic purification. Gratifyingly, this reductive amination reaction also worked well
with differently substituted orthophenylenediamines as depicted in Scheme 2. We did
not observe the formation of possible regio isomers in the examples reported. Also,
we did not see the formation of undesired bis alkylated compounds in the case of
4-chloro and 3-carbomethoxy substituted orthophenylenediamines.
The key intermediate 11 on subjecting to triphosgene-mediated cyclization in
dichloromethane (DCM) afforded imidazolone compound (13) in quantitative yield.
The imidazolone compound (13), on treatment with trifluoroacetic acid (TFA), fol-
lowed by basic aqueous workup, afforded boc-deprotected imidazolone (7) in quan-
titative yield. The imidazolone (7) on reductive amination with compound (8)[8b] in

M1 ALLOSTERIC AGONIST TBPB
1799
the presence of sodium triacetoxyborohydride afforded title compound TBPB (1) in
78% yield. The characterization data of the synthesized title compound comply with
1
the structure reported.[8] However, it was observed that both H NMR and 13C
NMR data reported for TBPB (1) by Lindsley et al.[8] do not comply with the struc-
ture. It was also noted that there was a sharp difference in the potencies between the
reported (289 nM, Emax ¼ 88%)[8] and the observed (1.5 nM, Emax ¼ 98%) value
(in-house synthesized compound evaluated at CEREP).
CONCLUSION
We have disclosed a simple and short synthetic protocol for TBPB (1) starting
with commercially available and economical starting materials. This protocol also
allows synthesizing more analogs that are otherwise difficult to obtain using the orig-
inally reported synthetic scheme. Discrepancies were observed in the reported[8]
NMR data for the title compound TBPB with the reported structure. A sharp differ-
ence in the reported and observed EC50 value was also noted.
EXPERIMENTAL
1
All the reagents used are purchased from Aldrich. Both H NMR and 13C
NMR spectra were recorded at 400 MHz on a Bruker NMR spectrometer instru-
ment (Fallanden, Switzerland). All mass spectra were recorded using the electrospray
ionization (ESI) technique on API 2000, ABS triple quadrupole instrument
(MDS-SCIEX, Concord, Ontario, Canada). Infrared (IR) spectra were recorded
on KBr discs and in solid state using an IR Pristage 2 instrument from Shimadzu.
Elemental analysis was performed on Elementar GmbH, Vario microcube instru-
ment. Column chromatography was performed using 100 to 200-mesh silica gel.
Analytical high-performance liquid chromatography (HPLC) was done using Agi-
lant systems (Model-1100 series). Differential scanning calorimetry (DSC) data were
recorded on a Waters DSC Q100 instrument.
General Representative Reductive Amination Procedure: Synthesis
of tert-Butyl 4-(2-Amino Anilino)piperidine-1-carboxylate (11)
1-Boc-4-piperidone (1.10 g, 5.54 mmol) and acetic acid (0.28 mL, 4.6 mmol)
were added to a stirred solution of ortho-phenylenediamine (500 mg, 4.62 mmol) in
DCM (18.5 mL) cooled at 0 ꢀC. The resulting mass was stirred for 15 min and then
sodium triacetoxyborohydride (2.94 g, 13.8 mmol) was added. The reaction mixture
was gradually warmed to rt and stirred for 16 h before quenching with aqueous
NaHCO3 solution. The two layers were separated and the aqueous layer was
extracted with DCM. The combined organic layer was washed with brine and dried
over anhydrous Na2SO4, and the volatiles were removed under reduced pressure.
The crude product was purified by silica-gel column to obtain mono-alkylated
compound 11 (830 mg) and bis-alkylated compound 12 (470 mg) in 62 and 21%
yields respectively.

1800
M. A. RASHEED, N. M. SHAIK, AND R. NIROGI
Compound 11
DSC: 107.22 ꢀC; IR (KBr) t 3439, 3370, 2973, 2926, 2856, 1665, 1600, 1520,
1429, 1166, 1149, 861, 767, 730 cmꢁ1
;
1H NMR (CDCl3): d 6.83 (t, J ¼ 7.4 Hz,
1H), 6.80–6.68 (m, 3H), 4.18–4.0 (m, 2H), 3.48–3.39 (m, 1H), 3.07–2.91 (m, 2H),
2.11–2.0 (m, 2H), 1.49 (s, 9H), 1.45–1.32 (m, 2H); 13C NMR (100 MHz, CDCl3): d
154.7, 135.9, 134.8, 120.4, 119.0, 116.9, 113.2, 79.4, 50.0 (2C), 42.5, 32.3 (2C),
28.3; mass (m=z): 292.4 (M þ H)þ. Anal. calcd. for C16H25N3O2: C, 65.95, H, 8.65,
N, 14.42. Found: C, 65.88, H, 8.57, N, 14.53.
Bis-Alkylated compound 12
1H NMR (CDCl3): d 7.16–7.09 (m, 2H), 7.08–7.02 (m, 2H), 4.45–4.20 (m, 4H),
3.96–3.85 (m, 2H), 3.0–2.82 (m, 4H), 2.18–2.05 (m, 4H), 1.82–1.70 (m, 4H), 1.51 (s,
18H); 13C NMR (100 MHz, CDCl3): d 154.8, 136.9, 118.9, 108.9, 79.6, 51.6, 33.6,
28.4; mass (m=z): 475.3 (M þ H)þ. Anal. calcd. for C26H42N4O4: C, 65.79; H, 8.92;
N, 11.80. Found: C, 65.85; H, 9.09; N, 12.02.
Synthesis of 1-[1’-(2-Methylbenzyl)-[1,4’]bipiperidinyl-
4-yl]-1,3-dihydrobenzimidazol-2-one (1, TBPB)
Compound 7 (1.17 g, 5.41 mmol) and acetic acid (0.56 mL, 9.85 mmol) were
added to a stirred solution of compound 8[8b] (1.0 g, 4.92 mmol) in DCM (20 mL)
cooled at 0 ꢀC. The resulting mass was stirred for 1 h followed by portionwise
addition of sodium triacetoxyborohydride (3.13 g, 14.78 mmol). The reaction mix-
ture was gradually warmed to rt and stirred for 16 h before quenching with aqueous
NaHCO3 solution. The two layers were separated, and the aqueous layer was
extracted with DCM. The combined organic layer was dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure to obtain the crude
mass, which was purified by silica-gel column chromatography to obtain the title
compound TBPB (1.56 g) in 78% yield. DSC: 199.86 ꢀC; IR (KBr) t 3131, 2956,
2925, 2868, 2760, 1697, 1485, 1380, 1089, 754, 730, 699 cmꢁ1; 1H NMR (DMSO-d6):
d 10.81 (s, 1H), 7.26–7.15 (m, 2H), 7.15–7.05 (m, 3H), 6.98–6.90 (m, 3H), 4.15–4.03
(m, 1H), 3.37 (s, 2H), 3.05–2.92 (m, 2H), 2.88–2.78 (m, 2H), 2.38–2.20 (m, 5H), 2.29
(s, 3H), 2.0–1.90 (m, 2H), 1.80–1.70 (m, 2H), 1.70–1.60 (m, 2H), 1.50–1.38 (m, 2H);
13C NMR (100 MHz, DMSO-d6): d 154.0, 137.3, 137.0, 130.3, 129.7, 129.5, 128.6,
127.1, 125.7, 120.7, 120.6, 109.1, 109.0, 61.8, 60.5, 53.3 (2C), 50.7, 48.8 (2C), 29.4
(2C), 28.2 (2C), 19.1; mass (m=z): 405.4 (M þ H)þ. Anal. calcd. for C25H32N4O:
C, 74.22; H, 7.97; N, 13.85. Found: C, 74.28; H, 7.86; N, 14.0. HPLC purity:
99.01%. EC50: 1.5 nM (Emax ¼ 98%, CEREP data).
Complete experimental details are available online in the Supplemental
Material.
ACKNOWLEDGMENT
The authors are thankful to Venkat Jasti, CEO, Suven Life Sciences Limited,
for financial support and encouragement.

M1 ALLOSTERIC AGONIST TBPB
1801
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