Scalable preparation of benzimidazole compounds

Article abstract of DOI:10.1080/00397910701845837

The preparation of benzimidazole compound 7, an ORL-1 agonist, is described. The four-step procedure gave the compound 7 in 29% overall yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701845837

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Scalable Preparation of Benzimidazole
Compounds
Noriaki Murase a , Yoshinori Murata a , Toyoharu Numata a & Kunio Satake a
a Department of Pharmaceutical Science, Chemical Research and
Development Group, Pfizer Global Research and Development, Aichi, Japan
Published online: 25 Apr 2008.
To cite this article: Noriaki Murase , Yoshinori Murata , Toyoharu Numata & Kunio Satake (2008) Scalable
Preparation of Benzimidazole Compounds, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:9, 1478-1484, DOI: 10.1080/00397910701845837
To link to this article: http://dx.doi.org/10.1080/00397910701845837
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Synthetic Communicationsw, 38: 1478–1484, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845837
Scalable Preparation of Benzimidazole
Compounds
Noriaki Murase, Yoshinori Murata, Toyoharu Numata,
and Kunio Satake
Department of Pharmaceutical Science, Chemical Research
and Development Group, Pfizer Global Research and Development,
Aichi, Japan
Abstract: The preparation of benzimidazole compound 7, an ORL-1 agonist, is
described. The four-step procedure gave the compound 7 in 29% overall yield.
Keywords: Amination, benzimidazole, chlorination
Benzimidazole compound 7 was found to be a potent ORL-1 agonist in
structure activity relationship (SAR) studies to prepare analgesic
compounds through opioid receptors, especially the ORL1 receptor. The
medicinal chemical synthetic route is shown in Scheme 1. Each step in the
synthesis was further optimized to support an exploratory bulk campaign of
the compound 7 as described. In a previous article we reported the optimal
condition for the Strecker reaction, using TsOH as an acid to prepare a-ami-
nonitrile 3 in good yield.[1] Herein, we report the results of our process
research and scale-up to prepare the desired compound 7 from compound 3
(Scheme 2).
First, the nitrile group in 3 was displaced with PhMgBr.[2] During the
addition of PhMgBr to a mixture of 3 in tetrahydrofuran (THF), the suspension
gradually turned into a clear solution. Dimethoxyethane (DME) was the best
Received September 6, 2007
Address correspondence to Yoshinori Murata, Department of Pharmaceutical
Science, Chemical Research and Development Group, Pfizer Global Research and
Development, 5-2 Taketoyo, Aichi 470-2393, Japan. E-mail: japan_ym@yahoo.co.jp
1478

Preparation of Benzimidazole
1479
Scheme 1. Synthesis of compound 7.
solvent, and in combination with a lower temperature during the addition of
PhMgBr, gave 4 in the best yield. Five equivalents of a saturated aqueous
NH4Cl solution were needed to quench the reaction mixture and remove almost
all of the Mg salts (0.2 w/w%). If this procedure was not followed, the next
step of chlorination did not work well. (When 1.4 w/w% of Mg was present
with compound 4, the chlorination reaction did not go to completion and approxi-
mately 50% of 4 remained as determined by high performance liquid chromato-
graphy (HPLC) analysis.) Processing on this scale gave 4 in 85% yield (94%
purity based on HPLC analysis) as a white solid after a reslurry in THF.
To prepare compound 5, chlorination of 4 was accomplished with neat
POCl3 at reflux.[3] To isolate and purify compound 5, excess POCl3 was
Scheme 2. Conversion of compound 3 to compound 7.

1480
N. Murase et al.
Scheme 3. Plausible mechanism of the reaction of 4 with POCl3.
removed under reduced pressure to be a more effective process on a larger scale.
Subsequent filtration through basic alumina helped to remove minor polar impu-
rities. (These polar impurities were unknown.) Overall, this procedure provided
5 in 40% yield as a solid. The low yield for this step may be attributable to an
unproductive side reaction with POCl3 to form the undesired compound 8,
which could not be isolated or detected directly (Scheme 3). In addition,
compound 8 seems to be converted to compound 12 after quenching the
reaction with aq. NaOH, based on MS analysis. Support for this hypothesis
comes from the reaction of 4 with chlorophosphonates, which gave only
compound 13 instead of compound 14 (Scheme 4).[4] In addition, at a longer
reaction time, compounds 10 and 11 which were generated from compound
1
5, were observed by H NMR and/or mass spectroscopy (MS) analyses.
Therefore, on this scale, the optimal reaction time for this reaction was for 2 h.
Recently, the chlorination of hydroxypyridine derivatives using P2O5 and
nBu4NCl has been reported.[5] Unfortunately, this procedure failed to afford
the desired product 5.
For the final amination, 12 equiv. of 1-methylpiperazine (6) were needed
to drive the reaction almost to completion.[3e] In the crude product, only trace
Scheme 4. Reaction of 4 with chlorophosphonates.

Preparation of Benzimidazole
1481
amounts of 4 were observed but they could be removed by a reslurry in hot
isopropanol (IPA)/EtOH. (Residual solvent (CH2Cl2 and EtOAc) was not
completely removed by a reslurry with IPA. Please see the experimental
section.) After filtration and drying, the desired product 7 was obtained in
88% yield as a white solid. Based on HPLC analysis, only one unknown
impurity (0.1%) was observed.
In conclusion, a concise four-step synthesis to prepare the compound 7
has been developed. This proceeded in 29% overall yield and did not
require column chromatography for purification.
EXPERIMENTAL
NMR (1H, 13C) spectra were obtained using JMN-GX270, JEOL. Chemical
shifts are reported in parts per million (ppm) with reference to internal
solvent. HPLC (High Performance Liquid Chromatography) was recorded
on Alliance 2960, Waters. MS (Mass Spectroscopy) was recorded on
Automass 1, JEOL.
Compound 4
Over 1.5 h, 1.0 M PhMgBr in THF (4.8 L, 4.8 mol, Aldrich) was added to a
mixture of 3 (676 g, 2.0 mol)[1] and DME (3.4 L, 5.0 vol) in an ice bath.
During the addition, the mixture turned into a solution, the internal temperature
rose to ca. 78C, and then solids appeared. This mixture was heated at 508C for 2 h
(HPLC result of aliquot showed that the ratio between 4 and 3 was ca 10:1).
After cooling, 1.5 M aq. NH4Cl solution (prepared by NH4Cl, 642 g; and
H2O, 8 L) was added gradually over 1 hr to the reaction mixture. The addition
was exothermic and the final pH of the aqueous layer was ca. 9–10. Hexane
(7.5 L, 11 vol) was added and the mixture was stirred at rt for 2 h. The precipi-
tated solids were collected by filtration, and the obtained solid was washed with
H2O (1.5 L) and hexane (1.5 L) and then dried in a vacuum oven (708C, 24 h) to
afford crude 4 (744 g, 96%, 4:3 ¼ ca. 10:1 based on HPLC analysis).
A mixture of crude 4 (1.22 kg) in THF (6.1 L, 5.0 vol) was heated at
reflux for 2 h. After cooling, the mixture was filtered, and the solids were
washed with THF (3 L) and hexane (1 L) and then dried in a vacuum oven
(708C, 3 days) to give 4 (1.1 kg, total 85%) as a white solid. By HPLC
analysis, the material is 94% pure and contains ca. 5.6% of 3 and/or 1 as
well as 0.4% unknown impurities. Ash analysis: ca. 0.2 w/w%.
HPLC condition: 210 nm, column; Kromasil, eluent; CH3CN/0.3%
1
HClO4 ¼ 40:60, 1 mL/min; H NMR (270 MHz, d-DMSO): d 10.80 (brs,
1H), 7.55–7.45 (m, 2H), 7.40–7.30 (m, 2H), 7.25–7.15 (m, 2H), 7.02–6.92
(m, 3H), 4.10–3.95 (m, 1H), 2.95–2.80 (m, 2H), 2.30–1.90 (m, 8H), 1.80–
1.35 (m, 10H). MS m/z 389: IR (KBr) 3394, 1697 cm21
.

1482
N. Murase et al.
Compound 5
A mixture of 4 (200 g, 513 mmol) and POCl3 (1.0 L, 10.7 mol) was stirred at
1108C for 2 h under N2. After cooling to 608C, excess POCl3 was removed by
distillation under reduced pressure (80 mmHg then 60 mm Hg). The residue
was cooled and dissolved in anhydrous CH2Cl2 (2.0 L). The resulting
solution was added, with vigorous stirring, to a 2 N aq. NaOH (6.5 L)
solution at such a rate as to maintain the temperature at 10 to 158C. After
the addition was complete, the mixture was neutralized by the careful
addition of 2 N aq.HCl (1.1 L), then CH2Cl2 (2.8 L) and water (1.2 L). The
resulting mixture was stirred at rt for 1 h and after settling, the two layers
were separated. The aqueous layer was extracted with CH2Cl2 (1.5 L ꢀ 2).
The combined organic phases were dried over Na2SO4 (3.7 kg) and filtered
through a Celite padw (500 g). Basic alumina (900 g) was added to the
filtrate and it was concentrated. The residue was dried under vacuum for
1 h. EtOAc (8.5 L) was then added and the resulting mixture was stirred for
1 hr at rt then filtered through a Celite padw (800 g). The filtrate was concen-
trated, and the residue was dissolved in isopropyl ether (IPE) (10 L). The
solvent was removed (ca. 5.5 L) by distillation at normal pressure, and a pre-
cipitate had appeared. This reaction mixture was cooled gradually to rt and
filtered to give 62.8 g (30%) of colorless crystalline 5. The filtrate was concen-
trated and the residue was recrystallized from IPE with the same procedure
described previously to give 19.9 g (10%, 40% total) of 5.
1H NMR (270 MHz, CDCl3): d 7.71–7.63 (m, 2H), 7.61–7.47 (m, 2H),
7.39–7.18 (m, 5 H), 4.43–4.26 (m, 1H), 3.10–2.92 (m, 2H), 2.45–2.20
(m, 4H), 2.15–2.00 (m, 4H), 1.90–1.67 (m, 4H), 1.65–1.40 (m, 6H).
Compound 7
A mixture of 1-methylpiperazine (6) (420 mL, 3.8 mol) and 5 (129 g,
316 mmol) was stirred at 1208C for 28 h under N2. The reaction mixture
was allowed to cool to 608C. At this point, a precipitate had formed and the
mixture was diluted with EtOAc (2 L), then cooled to rt. With vigorous
stirring, the reaction mixture was poured into a mixture of 0.33 N aq.
NaOH (3.1 L), EtOAc (1 L) and CH2Cl2 (0.5 L). After settling, the two
layers were separated, washed with dilute aq. NaCl solution, dried over
Na2SO4 (500 g) and filtered. The filtrate was concentrated, and the residue
was diluted with CH2Cl2 (0.5 L) and EtOAc (2 L). The resulting solution
was warmed at 608C, and the solvent was removed by distillation. After dis-
tilation (ca. 600 mL), a precipitate formed. The mixture was cooled to rt and
stirred under N2 for 2 days. The precipitate was collected by filtration, and the
solid was washed with EtOAc (0.3 L) and dried under reduced pressure at rt
for 18 h to give 7 (120 g) as a white solid. A small amount (ꢀ1%) of 5
could also be detected by HPLC analysis.

Preparation of Benzimidazole
1483
Purification
A mixture of crude 7 (189 g) and 2-propanol (0.5 L) was stirred at 508C for 5 h
and at rt for 14 h under N2. The precipitated solids were collected by filtration
and dried under reduced pressure at 508C for 3.5 h.
For further purification, a mixture of 7 (184 g) in 2-propanol (1 L) and
EtOH (0.5 L) was stirred at 508C for 12 h under N2. Similar treatment gave
the desired product 7 (176 g, total 88%) as a white solid.
TLC: Rf ¼ 0.22, CH2Cl2/MeOH ¼ 10/1, silica-gel plate Merck 60F254,
mp 182.8–183.58C, 1H NMR (600 MHz, CDCl3): d 7.62–7.60 (m, 1H), 7.52
(d, 2H, J ¼ 7.8 Hz), 7.50 (m, 1H), 7.34 (t, 2H, J ¼ 7.9 Hz), 7.22 (t, 1H,
J ¼ 7.2 Hz), 7.15–7.12 (m, 2H), 4.10–4.03 (m, 1H), 3.24 (t, 4H,
J ¼ 4.9 Hz), 3.00 (d, 2H, J ¼ 10 Hz), 2.61 (like br.s, 4H), 2.37 (s, 3H), 2.23
(t, 2H, J ¼ 11 Hz), 2.14–2.06 (m, 4H), 1.79–1.76 (m, 2H), 1.68 (d, 2H,
J ¼ 11 Hz), 1.62–1.50 (m, 8H). 13C NMR (150 MHz, CDCl3): d 157.5,
148.1, 141.9, 133.2, 127.8, 127.1, 126.1, 121.2, 120.9, 118.5, 111.6, 65.9,
54.8, 54.7, 51.2, 46.7, 46.1, 35.0, 31.2, 30.5, 24.5. IR (KBr) 2936, 2795,
1522, 1456, 1400, 1286, 1254, 1136, 1011 cm21 HRFAB-MS (m/z) found
472.3446 (M þ H)þ calcd. 472.3434 (for C30H42N5). Anal. Calcd. for
C30H41N5: C, 76.39; H, 8.76; N, 14.85. Found: C, 76.33; H, 8.74; N, 14.84.
ACKNOWLEDGMENT
We thank Yoshiko Tsuda, Akemi Ando, Atsushi Omura, and Yoko Matsuoka
(Analytical R&D) for analytical support, Shinichi Sakemi (Structure Science
Group) for structural elucidation, and Stephane Caron (Pfizer Chemical R&D,
Groton) for useful discussion. We also thank Dave Whritenour (Pfizer
Chemical R&D, Groton) for proofreading this manuscript.
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