Identification, synthesis and characterization of impurities of (S)-Mitiglinide calcium dihydrate

Article abstract of DOI:10.14233/ajchem.2014.16137

(S)-Mitiglinide Calcium dihydrate (1), an important potent hypoglycemic agent. During laboratory optimization and later in bulk synthesis the formation of various impurities was observed. The method of preparation of most of these impurities is not availa

Full text of DOI:10.14233/ajchem.2014.16137

Asian Journal of Chemistry; Vol. 26, No. 8 (2014), 2417-2421
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16137
Identification, Synthesis and Characterization of Impurities of (S)-Mitiglinide Calcium Dihydrate
*
T. UMASANKARA SASTRY , K. NAGESWARA RAO, T. APPI REDDY and P. GANDHI
R&D Centre, Mylan Laboratories Limited, Anrich Industrial Estate, Bollaram (Village), Jinnaram (Mandal), Medak (District)-502 325, India
*Corresponding author: Tel: +91 9849961214: E-mail: umasankarasastry.tummalapalli@mylan.in
Received: 2 August 2013;
Accepted: 3 October 2013;
Published online: 15 April 2014;
AJC-15039
(S)-Mitiglinide Calcium dihydrate (1), an important potent hypoglycemic agent. During laboratory optimization and later in bulk synthesis
the formation of various impurities was observed. The method of preparation of most of these impurities is not available in literature. We
describe herein the formation, synthesis, preparation and characterization of these impurities.
Keywords: Mitiglinide Calcium, Regio isomer, Impurities, Hypoglycemic agent.
synthetic details have been reported and the impurities are not
commercially available. In this context, the present study
describes identification, synthesis and characterization of
impurities of (S)-mitiglinide calcium dihydrate.
INTRODUCTION
(S)-Mitiglinide calcium dihydrate (1), calcium (2S)-2-
benzyl-4-[(3aR,7aS)-octahydro-2H-isoindol-2-yl]-4-
oxobutanoate hydrate (1:2:2), a novel hypoglycemic agent with
a chemical structure different from that of the sulfonylureas.
Mitiglinide inhibits the ATP-sensitive potassium channels in
pancreatic β-cells and stimulates insulin release. The configu-
ration of the stereogenic C-atom in the succinyl moiety is very
important for the activity of compound and the absolute (S)-
configuration is necessary for insulin secretory effect1-5. It is
useful for the treatment of type-2 diabetes.
Ph
O
H
H
O
OH
HO
-
Ca2+
.2H2O
O
N
O
O
2
1
6
(S)-Mitiglinide calcium dihydrate is designated chemically
as calcium (2S)-2-benzyl-4-[(3aR,7aS)-octahydro-2H-
isoindol-2-yl]-4-oxobutanoate hydrate (1:2:2). Its literature
synthesis6 (Scheme-I) involves dehydration of (S)-2-benzyl-
succinic acid (2) with acetic anhydride in the presence of
dichloromethane gives corresponding anhydride (3). Reaction
of (3) with cis-octahydroisondole (8) in presence of toluene
affords (S)-mitiglinide (4) which on treatment with anhydrous
calcium chloride in presence of sodium hydroxide and water
gives (S)-mitiglinide calcium dihydrate (1).
H
H
O
O-
Ca2+
O
N
O
O
O
2
7
10
H
H
O
O
N
Ca2+
N
Ca2+
O
H
O
H
O
O
2
2
During laboratory optimization of mitiglinide calcium
dihydrate (1), many process related impurities were detected
by HPLC analysis and their structure tentatively assigned as
6-16 on the basis of their LC-MS data. The guidelines recom-
mended by ICH state that the acceptable levels for a known
and unknown compound (impurity) in the drug should be less
than 0.15 and 0.10 %, respectively in an API7. In order to
quantify and limit the impurities in the final drug substance, it
is necessary to have standard for the impurities. However, no
12
14
H
H
O
N
-
O
O
16
Mitiglinide calcium dihydrate (1) and process related impurities

2418 Sastry et al.
Asian J. Chem.
7.34 (m, 1H), 3.51-3.62 (m, 1H), 3.10-3.16 (dd, J = 13.8 and
4.8, 1H), 2.85-2.99 (m, 1H), 2.72-2.80 (dd, J = 18.3 and 6.6,
1H). 13C NMR : 174.59, 171.39, 137.86, 128.79, 128.56,
126.66, 41.79, 34.91, 33.54. ESI-MS: m/z 191 ([M + H]+,
C11H10O3 calcd. 190), m/z 189 ([M-H]-).
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Bruker
300 MHzAvance NMR spectrometer; the chemical shifts were
reported ppm relative to either residual solvent or tetramethyl-
silane. The FT-IR spectra were recorded on Perkin-Elmer
Spectrum one FT-IR spectrometer and only prominent peaks
are reported. Mass spectra were recorded on a Agilent 1100
series LC-MSD-TRAP-SL system. HPLC analysis was carried
out on WatersAlliance 2487 or WatersAlliance 2695 systems.
All the reagents used were of LR grade and used without further
purification.All the anhydrous reactions were carried out under
a nitrogen atmosphere. Silica gel (120-200 mesh) was used
for column chromatography.
Calcium bis{(2R)-2-benzyl-4-[(3aR,7aS)-octahydro-
2H-isoindol-2-yl]-4-oxobutanoate} (or) (R)-mitiglinide
calcium (10): To a suspension of (R)-benzylsuccinic anhydride
7 ( 15 g, 78.9 mmol) in toluene (150 mL), was heated to 45-
47 °C and added cis-octahydroisoindole 8 (11.8 g, 94.6 mmol).
The reaction mixture was stirred for 0.5 h, analytical HPLC
revealed the absence of the starting material and the formation
of regioisomer along with (R)-mitiglinide. The reaction
mixture was cooled to room temperature and stirred for 1 h.
Filtered the unwanted regioisomer and washed with toluene
(15 mL). To the toluene filtrate added sodium hydroxide
solution (2.85 g in 75 mL water) and stirred for 15 min. The
layers were separated and the organic layer was extracted with
water (15 mL). The combined aqueous layer was mixed with
ethanol (150 mL) and slowly added calcium chloride solution
(6.6 g in 210 mL water) at room temperature. The white preci-
pitate was filtered, washed with purified water (30 mL) and
dried. The dried (R)-mitiglinide calcium crude was recrysta-
llized from 95 % ethanol to afford pure (R)-mitiglinide calcium
10 (9 g , 34.3 % yield). IR (KBr, νmax, cm-1) : 3060, 3026,
2926, 2853, 1621, 1562, 1447, 1435, 1336, 1282, 1200, 1186,
General experimental procedure
(2R)-2-Benzylbutanedioic acid (or) (R)-2-benzylsuccinic
acid (6): To a solution of (R, S)-2-benzylsuccinic acid (60 g,
288 mmol) 5 in ethanol (720 mL) was added (S)-α-methyl-
benzylamine (35 g, 289 mmol) at 28-30 °C and the mixture
was stirred for 5 h at 28-30 °C. The salt was filtered and then
washed with ethanol (60 mL). The wet material was dried at
40-45 °C for 5 h. The dried material was suspend in ethanol
(100 mL) then mixture was heated to 55-60 °C and stirred for
2 h then cooled to 28-30 °C. The salt was filtered and then
washed with ethanol (20 mL). Dry the wet material under
vacuum at 40-45 °C.To the suspension of the dried salt in
dichloromethane was added water. The pH was adjusted to 13
with 10 % sodium hydroxide solution (2.5 g in 25 mL) and
stirred for 10 min. The layers were separated and the aqueous
layer was washed with dichloromethane. The aqueous layer
pH was adjusted to 1-2 with 2N HCl (12 mL) and stirred for
3 h at 28-30 °C. Dry the product under vacuum for 5-6 h at
50-55 °C to afford (R)-2-benzylsuccinic acid 6 (8 g, 26.6 %
yield). IR (KBr, νmax, cm-1): 3032, 2953, 2918, 1712, 1603,
1
1074, 755, 746, 703. H NMR (DMSO-d6): δ 7.13-7.20 (m,
4H), 7.13-7.20 (m, 4H), 7.13-7.20 (m, 2H), 2.96-3.24 (m, 2H),
2.96-3.24 (m, 8H), 2.74-2.78 (m, 2H), 2.60-2.69 (m, 2H), 2.50-
2.55 (m, 2H), 2.04-2.12 (m, 2H), 2.04-2.12 (m, 4H), 1.27-
1.46 (m, 8H), 1.27-1.46 (m, 8H). 13C NMR: 181.67, 171.10,
141.11, 129.12, 127.87, 125.49, 49.35, 49.22, 44.56, 37.38,
36.76, 35.33, 35.20, 25.43, 25.11, 22.45, 22.17. ESI-MS: m/z
316 ([M + H]+, C38H48N2O6Ca, calcd. 315), m/z 314 ([M-H]–).
Calcium bis{(3R)-3-benzyl-4-[(3aR,7aS)-octahydro-2H-
isoindol-2-yl]-4-oxobutanoate} (or) (R)-mitiglinide calcium
regioisomer (12): To a suspension of (R)-benzylsuccinic
anhydride 7 (15 g, 78.9 mmol) in toluene (150 mL) was heated
to 45- 47 °C and added cis-Octahydroisoindole (8) (11.8 g,
94.6 mmol) at 45-47 °C. The reaction mixture was stirred for
0.5 h, whereupon TLC revealed the absence of starting material.
The reaction mixture was cooled to room temperature and
stirred for 1 h at 25-30 °C. Filtered the product and washed
with toluene (15 mL) and dried at 40-45 °C to obtained (R)-
mitiglinide regioisomer 11. To the dried material suspended
in purified water (25 mL) added sodium hydroxide solution
(2.80 in 50 mL water) at 25-30 °C. To the clear solution of the
reaction mass was added calcium chloride solution (6.6 g in
210 mL water) for 45 min at 25-30 °C. The white precipitate
was filtered and washed with water (30 mL) and dried. The
dried (R)-mitiglinide regioisomer was recrystallized from 95
% ethanol (270 mL) to afford pure (R)-mitiglinide calcium
regioisomer 12 (6.5 g, 24.7 % yield). IR (KBr, νmax, cm-1):
3061, 3027, 2926, 2856, 1621, 1600, 1549, 1464, 1409, 1336,
1
1497, 1457, 1450, 1433, 1295, 1241, 945, 872, 761, 705. H
NMR (DMSO-d6): δ 12.23 (br, s, 2H) 7.17-7.32 (m, 2H), 7.17-
7.32 (m, 2H), 7.17-7.32 (m, 1H), 2.85-2.94 (m, 1H), 2.85-2.94
(m, 1H), 2.69-2.77 (m, 1H), 2.38-2.46 (dd, J = 16.8 and 8.7,
1H), 2.20-2.27 (dd, J = 16.8 and 4.2, 1H). 13C NMR: 175.13,
172.89, 138.72, 128.93, 128.28, 126.32, 42.44, 36.89. ESI-MS:
m/z 231 ([M + Na]+, C11H12O4 calcd. 208), m/z 207 ([M-H]–).
(R)-Benzylsuccinic anhydride (or) (3R)-3-benzyldihy-
drofuran-2,5-dione (7): To a suspension of (R)-2-benzylsuccinic
acid 6 (25 g, 120 mmol) in dichloromethane (125 mL) was
added acetic anhydride (61.2 g, 599 mmol) at 25-30 °C. The
reaction mass was heated to 45-48 °C, the reaction mixture
was stirred at 45-48 °C and the progress of the reaction was
monitored by analytical TLC. After 3 h, TLC revealed the
completion of the reaction, then distilled out solvent completely
under vacuum at 50-55 °C. To the residue was added diisopro-
pylether (100 mL) and stirred for 1 h at 25-30 °C. The white
product formed was filtered and washed with diisopropylether
(50 mL). the wet material was dried under vacuum at 40-45
°C to afford (R)-benzylsuccinic anhydride 7 (21 g, 92 % yield).
IR (KBr, νmax, cm-1): 3085, 3065, 3027, 2979, 2931, 2875,
1870, 1844, 1771, 1602, 1494, 1456, 1412, 1299, 1289, 1250,
1
1311, 1244, 1231, 1185, 1074, 770, 744, 702. H NMR
(DMSO-d6): δ 7.11-7.25 (m, 4H), 7.11-7.25 (m, 4H), 7.17-
7.25 (m, 2H), 3.35-3.53 (m, 2H), 2.95- 3.12 (m, 2H), 2.95-
3.12 (m, 4H), 2.54-2.81 (m, 4H), 2.54-2.81 (m, 2H), 2.27-
2.41 (m, 2H), 1.88-2.13 (m, 2H), 1.88-2.13 (m, 4H), 0.61-
1
1237, 1214, 1081, 1060, 930, 889, 878, 848, 753. H NMR
(DMSO-d6): δ 7.21-7.34 (m, 2H), 7.21-7.34 (m, 2H), 7.21-

Vol. 26, No. 8 (2014)
Identification, Synthesis and Characterization of Impurities of (S)-Mitiglinide Calcium Dihydrate 2419
1.14 (m, 8H), 0.61-1.41(m, 8H). 13C NMR: 178.80, 173.45,
140.26, 128.87, 128.01, 125.78, 49.98, 48.88, 42.54, 40.42,
38.94, 36.36, 35.22, 25.29, 24.66, 22.93, 21.19. ESI-MS: m/z
316 ([M + H]+, C38H48N2O6Ca, calcd. 315), m/z 314 ([M-H]-).
Calcium bis{(3S)-3-benzyl-4-[(3aR,7aS)-octahydro-
2H-isoindol-2-yl]-4-oxobutanoate} (or) (S)-mitiglinide
calcium regioisomer (14): To (S)-benzylsuccinic anhydride
3 (15 g, 78 mmol), anhydrous toluene (150 mL) was added
and heated to 45-47 °C. Slowly added cis-octahydroisoindole
(8) (11.8 g, 94.6 mmol) for a period of 10-15 min at 45-47 °C,
when analytical HPLC showed the absence of starting material
and the formation of (S)-regio isomer along with (S)-miti-
glinide. The reaction mixture was cooled to 25-30 °C and
stirred for 1 h. Filtered the regioisomer and washed with toluene
(15 mL), dried at 45-50 °C to afford (S)-mitiglinide regio-
isomer 13. To the dried material purified water was added (25
mL) and slowly added sodium hydroxide solution (2.8 g in 50
mL water) at 25-30 °C. To the obtained clear solution calcium
chloride solution was added (5.49 g in 175 mL water) at 25-
30 °C. The reaction mixture was stirred for 10 h at 25-30 °C.
Filtered the white precipitate and washed with water (50 mL).
The wet material was dried at 45-50 °C. The dried material
was suspended in ethanol (120 mL) was heated to reflux to
get clear solution. To the clear solution water was added (6 mL)
at 80-85 °C. The reaction mixture was slowly cooled to 25-
30 °C and stirred for 4 h at 25-30 °C. The white precipitate
was filtered and washed with ethanol (6 mL) and dried under
vacuum at 45-50 °C to afford (S)-mitiglinide calcium regio-
isomer 14 (6.0 g , 23.0 % yield). IR (KBr, νmax, cm-1): 3061,
3027, 2926, 2856 1621, 1601, 1550, 1464, 1416, 1336, 1312,
1231, 1185, 1075, 814, 795, 769, 701. 1H NMR (DMSO-d6):
δ 7.17-7.25 (m, 2H), 7.11-7.25 (m, 4H), 7.11-7.25 (m, 4H),
3.34-3.53 (m, 2H), 2.95-3.18 (m, 4H), 2.95-3.18 (m, 2H), 2.55-
2.84 (m, 4H), 2.55-2.84 (m, 2H), 2.27-2.40 (m, 2H), 1.88-2.12
(m, 2H), 1.88-2.12 (m, 2H), 0.62-1.41 (m, 8H), 0.62-1.41 (m,
8H). ESI-MS: m/z 316 ([M + H]+, C38H48N2O6Ca calcd. 315), m/z
338 ([M + Na]+), m/z 314 ([M-H]-.
RESULTS AND DISCUSSION
(S)-Mitiglinde calcium dihydrate 1 synthesized is shown
in Scheme-I. Dehydration of (S)-2-benzylsuccinic acid 2 with
acetic anhydride gives corresponding (S)-Benzylsuccinic
anhydride 3. The reaction of 3 with cis-octahydroisoindole 8
in the presence of toluene gives (S)-mitiglinide 4, which upon
treatment with anhydrous calcium chloride in presence of
sodium hydroxide and water afforded (S)-mitiglinide calcium
dihydrate 1.
Ph
O
OH
i
HO
O
O
O
O
(
S
)-2-benzylsuccinic acid
(2)
(
S
)-3-benzyldihydrofuran-2,5-dione
(3)
ii
H
H
O
H
H
O
O
iii
OH
.2H2O
Ca
N
N
O
O
2
(
1)
(4)
Calcium (I) (2S)-2-benzyl-4
-((3a,R,7aS)-octahydro-1H-inden-2-yl)
-4-oxobutanoate Dihydrate
(2S)-2-benzyl-4-((3a,R,7aS)
-octahydro-1H-inden-2-yl)
-4-oxobutanoate acid
Scheme-I:Reagents and conditions: (i) Dichloromethane, acetic anhydride,
40-45 °C; (ii) cis-Octahydroisoindole, toluene, 40-45 °C; (iii)
NaOH, H2O, calcium chloride, ethanol
In Laboratory Optimization of (S)-mitiglinide calcium,
many process related impurities were identified and their
synthesis was undertaken. During the resolution of (R,S)-2-
benzylsuccinic acid 5 with (R)-α-methyl benzylamine,
formation of 2-4 % of the undesired R-isomer was observed
when analyzed by Chiral-HPLC, its corresponding carry over
throughout the synthesis leads to contamination of (S)-miti-
glinide calcium with (R)-isomer impurity. (R)-2-Benzyl-
succinic acid impurity 6 was synthesized by the resolution of
(R,S)-2-benzylsuccinic acid 5 with (S)-α-methyl benzylamine
in the presence of dichloromethane. The resulting amine salt
was liberated by sodium hydroxide in the presence of water and
dichloromethane, followed by the aqueous phase acidification
(2S)-2-Benzyl-4-[(3aS,7aS)-octahydro-2H-isoindole-2-
yl]-4-oxobutanoic acid (16): To a suspension of (S)-benzyl-
succinic anhydride 3 (9 g, 78 mmol) in toluene (90 mL) was
heated to 45-47 °C and trans-octahydroisoindole solution (7 g
in 45 mL) was added drop wise at 45-47 °C. The reaction
mixture was stirred at 45-47 °C and the progress of the reaction
was monitored by analytical TLC. After 0.5 h, TLC revealed
the completion of the reaction. The reaction mass was cooled
to 25-30 °C and stirred for 1 h. Filtered the material, washed
with toluene (5 mL) and dried at 45-50 °C to yield the trans
mitiglinide (16) (2.0 g, 22 % yield). IR (KBr, νmax, cm-1): 3419,
3082, 3025, 2927, 2872, 2848, 1720, 1607, 1462, 1427, 1417,
1
to pH 1-2 with N HCl to get (R)-2-benzylsuccinic acid 6
(Scheme-II).
Ph
Ph
O
O
OH
1
OH
i
HO
1372, 1333, 1268, 1225, 1192, 1173, 748,703. H NMR
HO
(DMSO-d6): δ 12.13 (br,s 1H) 7.17-7.31 (m, 2H), 7.17-7.31
(m, 2H), 7.17 -7.31 (m, 1H), 3.44-3.58 (m, 2H), 2.57-2.96
(m, 2H), 2.57-2.96 (m, 2H), 2.57-2.96 (m, 1H), 2.40-2.50 (m,
1H), 2.18-2.27 (m, 1H), 1.71-1.82 (m, 2H), 1.71-1.82 (m, 2H),
1.06-1.46 (m, 2H), 1.06-1.46 (m, 2H), 1.06-1.46 (m, 2H).13C
NMR: 175.61, 168.66, 139.14, 128.91, 128.25, 126.22, 51.06,
50.28, 44.17, 42.67, 42.43, 37.16, 34.72, 28.07, 27.95, 25.17,
25.10. ESI-MS: m/z 316 ([M + H]+, C19H25NO3, calcd. 315),
m/z 338 ([M + Na]+).
O
O
(R)-2-benzylsuccinicacid
(6)
(R,S)-2-benzylsuccinic acid
(5)
Scheme-II: Reagents and conditions: (i) (S)-α-Methylbenzylamine,ethanol,
Dichloromethane, Conc HCl 25-30 °C
In Scheme-III, synthesis of (R)-benzylsuccinic anhydride
impurity 7 was prepared by the dehydration of (R)-2-

2420 Sastry et al.
Asian J. Chem.
benzylsuccinic acid (6) and acetic anhydride in the presence
of dichloromethane.
H
H
H
O
NH
i
+
N
HO
H
O
O
O
O
Ph
O
(
R
)-3-benzyl-4-((3a
H
R
H
,7aS
)-1
,7a
H-isoindol-
)-yl)-4
cis-Octahydro
isoindole
(R
)-3-benzyldihydrofuran
2(3H
-oxobutanoate
,3aH
,4H
,5
,6
,7
H
H
-2,5-dione
OH
i
(7)
(
11)
(8)
HO
ii
O
O
O
O
(R)-2-benzylsuccinic acid
(R)-3-benzyldihydrofuran-2,5-dione
H
(6)
O
(7)
N
Ca
Scheme-III: Reagents and conditions: (i)Aceticanhydride, Dichloromethane,
40-45 °C, Diisopropylether
O
H
2
O
calcium(I) (R)-3-benzyl-4-((3a
H
R,7a
)-yl)
S
)-1
-4-oxobutanoate
H-isoindol-
2(3H,3aH,4
,5H,6H,7H,7a
H
(R)-Mitiglinide calcium impurity8 10 is one of the potential
impurities aroused during the synthesis due the presence of
(R)-2-benzylsuccinic acid (6) as one of the impurities in the
(S)-2-benzylsuccinic acid (2). (R)-mitiglinide calcium was
synthesized by the condensation of (R)-2-benzylsuccinic
anhydride 7 with cis-octahydroisoindole (8) in the presence
of toluene gives (R)-mitiglinide (9), followed by the treatment
with anhydrous calcium chloride in the presence NaOH and
water, further recrystallization with 95 % aqueous ethanol gives
(R)-mitiglinide calcium (10) (Scheme-IV).
(12)
Scheme-V: Reagents and conditions: (i) Toluene, 40-45 °C (ii) NaOH, H2O,
calcium chloride, ethanol, 25-30 °C
During the condensation of (S)-benzylsuccinic anhydride
(3) with cis-octahydroisoindole (8) in the presence of toluene,
formation of 20-30 % undesired regioisomer was observed
when analyzed by HPLC. The (S)-mitiglinide calcium regio-
isomer impurity9 was synthesized by the condensation of (S)-
benzylsuccinic anhydride (3) and cis-octahydroisoindole 8 in
the presence of toluene. The resulting unwanted regioisomer
13 was filtered and dried, followed by reaction with anhydrous
calcium chloride in the presence of NaOH and water. The
obtained crude (S)-mitiglinide calcium regioisomer was further
purified with 95 % aqueous ethanol gives (S)-mitiglinide calcium
regioisomer (14) (Scheme-VI).
H
H
H
O
OH
i
N
+
NH
O
O
O
H
O
(
R
)-2-benzyl-4-((3a
2(3 ,3a ,4 ,5
oxobutanoic acid
R
,7a
S
)-1
H
H
-isoindol-
H
H
H
H
,6
H
,7
,7a
H
)-yl)
(R)-3-benzyldihydro-
furan-2,5-dion
Cis-Octahydro
isoindole
(
9)
H
(7)
H
(8)
O
ii
N
+
NH
HO
H
O
O
O
H
O
(
S
)-3-benzyl-4-((3a
R
,7aS
)-1
,7a
H
-isoindol-
)-yl)-
cis-Octahydro
isoindole
(S)-3-benzyldihydrof uran-
2(3
4-oxobutanoic acid
13
H
,3a
H
,4
H
,5
H
,6
H
,7H
H
H
H
O
2,5-dione
Ca
O
(3)
(8
)
(
)
N
O
ii
2
calcium(I) (
isoindol-2(3
R
H
)-2-benzyl-4-((3a
,3a ,4 ,5 ,6
4-oxobutanoate
10
R
,7a
H
S
,7a
)-1
H
H-
)
H
H
H
H
,7
H
O
(
)
N
Ca
Scheme-IV: Reagents and conditions: (i) Toluene, 40-45 °C (ii) NaOH, H2O,
calcium chloride, ethanol, 25-30 °C
O
H
2
O
calcium(I) (
2(3 ,3a ,4
S
H
)-3-benzyl-4-((3aR
,5 ,6 ,7 ,7aH)-yl)-4-
,7aS)-isoindol-
H
H
H
H
H
(R)-Mitiglinide calcium regioisomer 12 is one of the
potential impurity aroused due the presence of (R)-2-benzyl-
succinic acid impurity in (S)-benzylsuccinic anhydride (3).
During the condensation of (S)-benzylsuccinic anhydride with
cis-octahydroisoindole (8), there is a formation of 0.2-0.3 %
(R)-mitiglinide regioisomer was observed by analytical
HPLC. (R)-Mitiglinide calcium regioisomer 12 was prepared
by the condensation of (R)-benzylsuccinic anhydride 7 with
cis-octahydroisoindole (8) in the presence of toluene gives
(R)-mitiglinide regioisomer 11, followed treatment with
anhydrous calcium chloride in the presence of NaOH and
water to afforded (R)-mitiglinide calcium regioisomer (12)
(Scheme-V).
Scheme-VI: Reagents and conditions (i) Toluene, 40-45 °C (ii) NaOH, H2O,
calcium chloride, ethanol, 25-30 °C
In some of commercial samples, cis-octahydroisoindole
(8) was founded to be contaminated with traces of trans-
octahydroisoindole impurity (15), although the amount of
contamination of trans-mitiglinide impurity 16 in (S)-
mitiglinide calcium dihydrate (1) was never more than 0.15
%. The trans-mitiglinide impurity was synthesized by the
condensation of (S)-2-benzylsuccinic anhydride 3 with trans-
octahydroisoindole (15) in the presence of toluene to obtain
trans-mitiglinide impurity 16 (Scheme-VII).

Vol. 26, No. 8 (2014)
Identification, Synthesis and Characterization of Impurities of (S)-Mitiglinide Calcium Dihydrate 2421
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H
O
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H
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O
O
H
O
O
(S
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2(3 ,3a ,4 ,5 ,6
oxobutanoic acid
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S
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H
S
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H
H
H
H
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H
,7a )-yl)-4-
H
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(
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Scheme-VII: Reagents and conditions: (i) Toluene, 40-45 °C
Conclusion
For better knowledge of the synthetic path way of an active
pharmaceutical ingredient (API) it is mandatory to identify
all the impurities formed/anticipated. In this context we have
synthesized and characterized different potential process related
impurities of (S)-mitiglinide calcium dihydrate.
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ACKNOWLEDGEMENTS
The authors wish to thank Mylan Laboratories Limited
for supporting this work and also authorities of Jawaharlal
Nehru Technological University Hyderabad, Kukatpally,
Hyderabad-500 085.