Enantioseparation of benzazoles and benzanilides on polysaccharide-based chiral columns

Article abstract of DOI:10.1002/chir.20732

The chiral recognition ability of the polysaccharide-based chiral columns (Chiralpak AD-RH, Chiralpak AS-RJ, Chiralpak IC, Chiralcel OD-RH, and Chiralcel OJ-RH) for the benzazoles and the benzanilides was evaluated under reversed phase conditions. The columns showed the high chiral recognition ability for a wide range of benzazoles and benzanilides. Twenty-one racemates were used for the evaluation, and 20 racemates were completely separated on at least one of the columns. In particular, AS-RH and OJ-RH showed the high chiral recognition ability for the benzazoles, and the AD-RH, IC, and OJ-RH were effective for the benzanilides. 2009 Wiley-Liss, Inc.

Full text of DOI:10.1002/chir.20732

CHIRALITY 22:382–388 (2010)
Enantioseparation of Benzazoles and Benzanilides
on Polysaccharide-Based Chiral Columns
1
2
TAKATERU KUBOTA,1 NAOTAKA SAWADA, LILI ZHOU, AND CHRISTOPHER J. WELCH2
*
1Department of Process Research, Merck Research Laboratories, Merck & Co., Inc, Tsukuba, Ibaraki 300-2611, Japan
2Department of Process Research, Merck Research Laboratories, Merck & Co., Inc, Rahway, New Jersey 07065
ABSTRACT
The chiral recognition ability of the polysaccharide-based chiral col-
umns (Chiralpak AD-RH, Chiralpak AS-RJ, Chiralpak IC, Chiralcel OD-RH, and Chiralcel
OJ-RH) for the benzazoles and the benzanilides was evaluated under reversed phase
conditions. The columns showed the high chiral recognition ability for a wide range of
benzazoles and benzanilides. Twenty-one racemates were used for the evaluation, and
20 racemates were completely separated on at least one of the columns. In particular,
AS-RH and OJ-RH showed the high chiral recognition ability for the benzazoles, and the
AD-RH, IC, and OJ-RH were effective for the benzanilides. Chirality 22:382–388,
C
VV
2010.
2009 Wiley-Liss, Inc.
KEY WORDS: polysaccharide; chiral HPLC; resolution; benzazole; benzanilide
INTRODUCTION
In this study we focus on the enantioseparation of such
benzazole and benzanilide compounds having a chiral cen-
ter at the a-position using reversed phase chiral HPLC
analysis. Analysis using reversed phase chiral HPLC offers
a number of advantages, including compatibility with
biological matrices, facilitated sample preparation from
serum or plasma, and convenient interface with mass
spectrometry.26
The proportion of chiral compounds among new drug
candidates in the pharmaceutical industry has risen stead-
ily in recent years.1–3 Analysis of the enantiomeric purity
of chiral drug candidates is very important, because phar-
macological and toxicological properties are often different
for both enantiomers.4,5 The chromatographic separation
of enantiomers using high-performance liquid chromatog-
raphy (HPLC) with chiral stationary phases (CSPs) is one
of the most useful and popular techniques for enantiopur-
ity analysis. The main key for chiral HPLC is the chiral col-
umn, and more than 100 different commercial chiral col-
umns are already available in the market.6,7 Among these
chiral columns, the columns consisting of modified poly-
saccharide derivatives appear to be the most effective, and
are widely used in the world.8–11
In this study, the chiral recognition ability of commer-
cially available polysaccharide-based chiral columns (Chir-
alpak AD-RH, Chiralpak AS-RH, Chiralpak IC, Chiralcel
OD-RH, and Chiralcel OJ-RH (see Fig. 1) for a family of
benzazole and benzanilide-containing analytes was eval-
uated under reversed phase conditions. The benzazoles
(e.g., benzthiazoles, benzimidazoles, and benzoxazoles)
are widely distributed in nature, and play a significant role
as biologically active substance.12 Not surprisingly, the
benzazole moiety is often used as a key building block in
the synthesis of drugs and drug candidates.13–17 For exam-
ple, the benzimidazole structures are used for Proton
Pump Inhibitor drugs (PPI)13,14 such as Omeprazole18 and
Lansoprazole,19 and some of Angiotensin II Receptor
Blocker drugs (ARB)15 like Candesartan20,21 and Telmisar-
tan (see Fig 2).22–24 Benzanilides such as amino-benzani-
lide, hydroxyl-benzanilide, bromo-benzanilide, and sulfide-
benzanilide are starting materials for the corresponding
benzazoles (see Fig 3).16,17,25
EXPERIMENTAL
Instrument
An Alliance 2695 HPLC system (Waters Corp., Milford,
MA) equipped with a six-column selector valve, and con-
trolled by EmpowerTM software was employed for all the
experiments. The circular dichroism (CD) detector (CD-
2095) was purchased from JASCO Corp. (Tokyo, Japan).
Columns
Polysaccharide-based chiral columns, Chiralpak AD-RH,
Chiralpak AS-RH, Chiralpak IC, Chiralcel OD-RH, and
Chiralcel OJ-RH were purchased from Daicel Chemical
Industries, Ltd. (Tokyo, Japan). The structures of the poly-
saccharide derivatives are presented in Figure 1. Dimen-
sions and particle size for all columns were 150 3 4.6 mm
I.D. and 5 lm.
*Correspondence to: Takateru Kubota, Department of Process Research,
Merck Research Laboratories, Merck & Co., Inc, 3 Okubo, Tsukuba, Iba-
raki 300-2611, Japan. E-mail: Takateru_kubota@merck.com
Received for publication 3 February 2009; Accepted 6 March 2009
DOI: 10.1002/chir.20732
Published online 22 December 2009 in Wiley InterScience
(www.interscience.wiley.com).
C
VV
2009 Wiley-Liss, Inc.

ENANTIOSEPARATION OF BENZAZOLES AND BENZANILIDES
383
Fig. 1. Structures of polysaccharide derivatives used to chiral column.
Reagents
solved in extra-pure water (one liter), and then the pH of
the solution was adjusted with Sodium hydroxide aqueous
solution for 5 mM Boric buffer (pH 5 9.0). Benzazoles
and benzanilides (1–7 in Fig. 4) were synthesized by Pro-
cess Research Department at PreClinical Development
(Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan).25 The
products were identified with NMR and LC/MS. Acetoni-
trile-water (50/50) was used as a diluents for sample solu-
HPLC grade acetonitrile was obtained from Junsei
Chemical (Tokyo, Japan). Boric acid, phosphoric acid,
and sodium hydroxide aqueous solution were purchased
from Sigma-Aldrich (Milwaukee, WI). Extra-pure water
was prepared in-house with Milli-Q Gradient A-10 (Milli-
pore Corp., Billerica, MA). Phosphoric acid solution
(0.1%) was prepared by adding phosphoric acid (1 ml) to
extra-pure water (one liter). Boric acid (310 mg) was dis- tions.
Fig. 2. Structures of PPI and ARB drugs having benzimidazole moiety.
Chirality DOI 10.1002/chir

384
KUBOTA ET AL.
from the IC column is reversed relative to the elution
order observed on the other four columns. Understanding
the order of enantiomer elution from different chiral col-
umns is an important consideration in developing an opti-
mized method for chiral chromatographic analysis or puri-
fication.27 Interestingly, the CD detector response on the
OD-RH column clearly shows enantioseparation, although
only a single peak is observed with the UV detector. Pre-
sumably, compound 6b is slightly resolved on OD-RH, an
important finding that could easily be missed without CD
detection.
Fig. 3. Chemical conversion from benzanilide to benzazole.
The results for the enantioseparation of benzazoles (1–
3) on the five reversed phase CSPs are shown in Table 1.
Retention times (t1 and t2) for the two enantiomers, as
well as resolution factors, Rs [52(t2 2 t1)/(w1 1 w2)] are
calculated to compare the chiral recognition ability of the
different chiral columns. w1 and w2 are peak widths,
although the values are not described in the Table. On the
whole, the polysaccharide-based chiral columns recog-
nized each enantiomer of the benzazole analytes under
reversed phase conditions. All racemates of 1–3 were com-
pletely separated (Rs of 1.5) on at least one of the col-
umns. Compound 1b was baseline resolved on all chiral
columns, and particularly well resolved on Chiralpak AS-
RH (Rs 5 10.6).
An analysis of the data reveals that there is no single
column that separates the enantiomer of all benzazole
derivatives. A statistical comparison of the five reversed
phase CSPs for resolving the enantiomers of benzazole
enantiomers is shown in Table 2, revealing AS-RH and
OJ-RH as the columns affording the best resolution to the
most compounds, IC as the column affording greater than
baseline separation to the most compounds, and AD-RH
and AS-RH as the columns affording at least some resolu-
tion to the most compounds.
Column Screening
Column screening was performed with six-column selec-
tor valve for each compound, in order to evaluate the chi-
ral recognition ability of the columns efficiently. Five poly-
saccharide-based chiral columns and a PEEK union which
was used as a bypass were attached to the selector valve.
Eluent and gradient programs for column screening were
selected for each compound. The combination of extra-
pure water and acetonitrile was used for neutral com-
pounds (2, 3, 6, and 7). Phosphoric acid solution (0.1%)
and 5 mM Boric buffer (pH 5 9.0) were applied to acidic
compounds (5) and basic compounds (1 and 4), respec-
tively.26 The gradient program was changed, based on the
hydrophobicity of each compound. The other conditions
such as flow rate (1.0 ml/min), column temperature
(308C), and detector settings (254 nm for both UV and CD
detectors) were the same for all compounds.
RESULTS AND DISCUSSION
The structures of a group of 21 representative benzaole
and benzalinide compounds investigated in the study are
shown in Figure 4. The results of reversed phase chiral
HPLC screening with UV and CD detection for a represen-
tative benzanilide compound, 6b on the five polysaccha-
ride-based chiral columns (AD-RH, AS-RH, IC, OD-RH,
and OJ-RH) is shown in Figure 5. Compound 6b was com-
pletely separated on AD-RH, IC, and OJ-RH, and was par-
tially separated on AS-RH. Circular Dichroism (CD) detec-
tion shows that the order of elution of the enantiomers
Separation of the enantiomer of benzanilides (4–7) on
the five reversed phase chiral columns is summarized in
Table 3. These columns showed a similar ability to afford
enantioseparation for the benzanilides. Baseline resolution
of the enantiomers of all benanilides, 4–7, was obtained,
with the exception of compound 7a, which showed only
modest separation on AD-RH, AS-RH, IC, and OD-RH. The
enantiomers of compound 4c were resolved on all chiral
Fig. 4. Structures of benzazoles and benzanilides.
Chirality DOI 10.1002/chir

Fig. 5. Enantioseparation of 6b. Conditions: Eluent; A; H2O, B; MeCN, Gradient; 40%B (0 min)—80%B (30 min), flow rate; 1.0 mL/min, temp; 308C,
wavelength; 254 nm. The column and the detector used to each chromatogram are shown in the figure.

386
KUBOTA ET AL.
TABLE 1. Enantioseparation of benzazoles (1-3) on polysaccharide-based chiral columnsa
AD-RH
AS-RH
IC
OD-RH
OJ-RH
t1 (6)
(min)
t2
t1 (6)
(min)
t2
(min)
t1 (6)
(min)
t2
(min) Rs
t1 (6)
(min)
t2
t1 (6)
(min)
t2
(min)
(min) Rs
Rs
(min) Rs
Rs
1ab
1bb
1cb
7.4 (1)
15.7 (1)
14.6 (1)
6.3 (2)
8.3
18.0
14.9
6.9
2.0
5.9 (1)
6.7
19.0
14.0
5.3
2.7
5.7 (2)
7.9
17.4
13.3
5.9
7.0
6.9 (2)
9.4
18.5
17.1
6.1
7.5
4.7 (2)
4.9
14.2
15.1
Not
separated
NDe
2.8
2.4 13.8 (1)
ND 13.3 (1)
1.7
10.6 16.4 (2)
2.1 13.0 (2)
2.8
2.3 17.6 (1)
0.8 16.6 (1)
1.8
1.9 13.2 (1)
1.2 13.7 (1)
1.6
4.5
2ac,d
4.7 (1)
5.5 (2)
5.7 (2)
5.6
2bc
2cc
10.6 (2)
11.0 (1)
10.8
11.3
ND
ND
9.1 (1)
9.8 (1)
9.5
10.5
1.3 11.3 (2)
2.4
12.0
1.8 11.6 (2)
12.5 (1)
12.1
12.9
1.3
8.8 (1)
9.8
13.6
2.7
1.1
9.4
Not
1.2 13.2 (1)
separated
3ac
3bc
3cc
9.6 (1)
13.8 (2)
15.0 (1)
13.0
15.0
15.3
6.9
6.6 (1)
6.8
11.9
12.7
ND
1.0 14.1 (2)
0.9 11.9
7.2 (1)
8.1
3.5
8.5 (1)
4.2 15.2 (2)
16.7
10.3
15.4
5.7 8.3 (2)
ND 12.9 (2)
17.5 (1)
8.8
13.2
18.6
1.5
ND
2.7
1.9 11.5 (2)
ND 12.4 (1)
16.0
Not
separated
Not
separated
aFlow rate, 1.0 ml/min. Column temperature., 308C. The signs in parentheses represent the CD signal of the first-eluted enantiomer at 254 nm.
bEluent, A, 5 mM boric buffer (pH59.0); B, MeCN. Gradient, 20%B (0 min) 2 60%B (30 min).
cEluent, A, H2O; B, MeCN, Gradient, 40%B (0 min) 2 80%B (30 min).
dThe wavelength of CD detector is 233 nm.
eND: Not determined.
columns, and particularly well separated on OJ-RH (Rs 5 midizole, 1a was resolved on IC with an exceptional Rs
8.9). value of 7.0, but the corresponding benzanilide, 4a was
Compounds 7a, b, and c are in general poorly resolved not resolved at all on this column. The elution orders of 1
on the five columns, perhaps owing to nonspecific reten- were reversed between AD-RH and IC, while the elution
tion resulting from the large hydrophobic side chain pres- orders of 4 were the same. Clearly the change in structure
ent in these compounds. Nonspecific retention is generally brought about by the cyclization of the benzanilide to the
understood to decrease enantioselectiveity,28 in the chro- benzazole has a significant effect on the resulting chiral
matographic separation of enantiomers, and nonspecific separation.
hydrophobic retention has been shown to have a similar
deleterious effect on enantioseparation in the reversed
phase mode.26 In addition, compound 7 also contains an
additional stereocenter in this hydrophobic side chain.
CONCLUSION
Thus, a total of four possible stereoisomers are possible
Enantioseparation of the benzazoles and the benzani-
for compounds 7a, b, and c. However, at best, only two lides having a chiral center at the a-position was per-
peaks were observed for these analytes, and independent formed on a group of five commercially available polysac-
injections of material prepared from a single enantiomer of charide-based chiral columns (Chiralpak AD-RH, Chiral-
the hydrophobic side chain confirmed that the resolution pak AS-RH, Chiralpak IC, Chiralcel OD-RH, and Chiralcel
was due to the stereocenter at the a-position of benzani- OJ-RH). In general, the reversed phase chiral columns
lide, while the 2-ethyl-hexanol stereocenter was not recog-
nized.
TABLE 2. Statistical comparison of effectiveness of five
reversed phase chiral HPLC columns for resolution
A tabulation of the performance of the five columns for
reversed phase resolution of the enantiomers of the benza-
nilide family of compounds is shown in Table 4. AD-RH
of benzazole enantiomers
showed the broadest ability to resolve the enantiomers of
AD-RH
AS-RH
IC
OD-RH
OJ-RH
the entire range of benzanilides. Eight of 12 benzanilides
were completely resolved on AD-RH, and three benzani-
lides were partially resolved. On the other hand, IC and
OJ-RH showed unique chiral recognition ability. Although
several racemates were not separated at all, more than half
of benzanilides were best separated on IC or OJ-RH. AS-
RH showed the lowest chiral recognition ability for benza-
nilides among the five chiral columns, even though several
benzazoles were most recognized with this CSP.
No.a (%) No. (%) No. (%) No. (%) No. (%)
Rs ꢀ 1.5b
0 < Rs < 1.5
Rs 5 0
5
4
0
1
56
44
0
5
4
0
3
56
44
0
6
1
2
1
67
11
22
11
4
4
1
1
44
44
11
11
5
3
1
3
56
33
11
33
Highestc
11
33
aThe number of racemates, and the proportion. Total number of racemates
is nine.
bIn general, Rs > 1.5 means that the base-line separation is acheived. 0 <
Rs < 1.5 means that the parcially separation is acheived. Rs 5 0 means
that the separation is not acheived.
No significant trend was observed when comparing the
chiral separation result between a benzazole and the corre-
sponding benzanilide compound. For example, the benza- cThe number of the highest Rs value for each racemates.
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF BENZAZOLES AND BENZANILIDES
387
Rs
TABLE 3. Enantioseparation of benzanilides (4–7) on polysaccharide-based chiral columnsa
AD-RH
AS-RH
IC
OD-RH
OJ-RH
t1 (6)
(min)
t2
t1 (6)
t2
t1 (6)
t2
t1 (6)
t2
t1 (6)
(min)
t2
(min)
(min) Rs
(min)
(min) Rs
(min)
(min) Rs
(min)
(min) Rs
4ab
6.1 (1)
7.4 2.4
3.7 (2)
4.1 1.7
5.1
Not
5.0 (1)
5.4
1.4
4.3
Not
separated
separated
4bb 16.9 (1)
4cb 15.5 (1)
20.4
16.9
8.4
2.5 13.7 (2)
2.3 11.4 (1)
15.0
11.9
7.3
2.6 15.5 (1)
1.5 12.0 (1)
16.4
12.7
7.3
1.8 17.7 (2)
1.9 15.8 (1)
1.7
18.3
16.8
9.1
0.8 14.4 (1)
2.7 17.3 (1)
16.1
20.8
7.0
4.5
8.9
NDf
4.5
5ac
8.1 (2)
1.0
7.0 (2)
1.0
1.9
6.7 (1)
16.3
8.7 (1)
18.9 (1)
1.3
6.8 (1)
5bc 16.8 (1)
18.5
2.0 15.9 (1)
16.7
Not
separated
19.4
1.3 15.3 (1)
16.9
5cc 16.2 (1)
16.9
11.5
1.5 16.6 (1)
16.9
6.1
ND 13.5 (1)
1.2 8.2
14.1
Not
1.8 18.7 (1)
7.8 (2)
20.1
8.0
3.7 18.8 (2)
19.0
ND
6ad
9.7 (1)
6bd 11.5 (1)
3.3
3.6
5.8 (1)
8.8 (1)
9.6
ND
6.3
Not
separated
separated
13.7 3.8
14.7
9.3
1.4 12.1 (2)
12.8
Not
separated
14.0
9.1 (1)
10.3
3.7
6cd
7ac
11.8
Not
separated
Not
separated
6.4
11.0
Not
separated
13.2 (1)
9.9 (2)
12.9
2.1 13.1 (1)
15.4
5.5
9.9 (2)
10.5
13.9
11.9
0.9
6.2 (1)
7.1 (1)
8.3
ND 11.4 (2)
11.5
ND
10.2
ND
5.4
6.3 (1)
8.8
Not
separated
6.7 1.3
7be 10.7 (1)
7ce 11.8 (1)
2.3
7.4
0.9 13.9 (2)
15.8
3.5
Not
separated
14.5 2.0
ND
Not
separated
12.8
Not
separated
13.6 (1)
Not
separated
aFlow rate, 1.0 ml/min. Column temperature., 308C. The signs in parentheses represent the CD signal of the first-eluted enantiomer at 254 nm.
bEluent, A, 5 mM boric buffer (pH 5 9.0); B, MeCN. Gradient, 20%B (0 min) 2 60%B (30 min).
cEluent, A, 0.1% H3PO4 aq; B, MeCN. Gradient, 20%B (0 min) 2 60%B (30 min).
dEluent, A, H2O; B, MeCN. Gradient, 40%B (0 min) 2 80%B (30 min).
eEluent, A, H2O; B, MeCN. Gradient, 60%B (0 min) 2 90%B (30 min).
fND, not determined.
TABLE 4. Statistical comparison of effectiveness of five
reversed phase chiral HPLC columns for resolution
of benzanilide enantiomers
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8
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25
8
4
6
2
0
33
50
17
0
6
1
5
3
50
8
42
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4
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17
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Chirality DOI 10.1002/chir