Novel convenient synthesis of mitiglinide

Article abstract of DOI:10.1080/00397910701392590

A novel convenient synthesis of the hypoglycemic agent mitiglinide was developed. (2S)-4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-benzyl-butanoic acid (6) was prepared by selective hydrolysis of ethyl 4-[(3aR,7aS)-octahydro- 2H-isoindol-2-yl]-4-oxo-

Full text of DOI:10.1080/00397910701392590

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Novel Convenient Synthesis of Mitiglinide
Wei Huang a & Jun‐Da Cen a
a Department of Chemistry , Shanghai Institute of Pharmaceutical Industry ,
Shanghai, China
Published online: 03 Jul 2007.
To cite this article: Wei Huang & Jun‐Da Cen (2007) Novel Convenient Synthesis of Mitiglinide, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:13,
2153-2157, DOI: 10.1080/00397910701392590
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Synthetic Communicationsw, 37: 2153–2157, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701392590
Novel Convenient Synthesis of Mitiglinide
Wei Huang and Jun-Da Cen
Department of Chemistry, Shanghai Institute of Pharmaceutical Industry,
Shanghai, China
Abstract: A novel convenient synthesis of the hypoglycemic agent mitiglinide was
developed. (2S)-4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-benzyl-butanoic
acid (6) was prepared by selective hydrolysis of ethyl 4-[(3aR,7aS)-octahydro-2H-
isoindol-2-yl]-4-oxo-2-benzyl-butanoate (5) using a-chymotrypsin; the latter was
prepared by a novel facile route from (3aR,7aS)-octahydro-2H-isoindole. The overall
yield was 25.6%.
Keywords: a-chymotrypsin, mitiglinide, synthesis
Mitiglinide (calcium bis[(2S)-4-[(3aR,7aS)-octahydro-2H–isoindol-2-yl]-4-
oxo-2-benzylbutanoate]dihydrate) is a novel oral hypoglycemic agent. It
inhibits the adenosine triphosphate (ATP)-sensitive potassium channels in pan-
creatic b-cells and stimulates insulin release like sulfonylureas,[1] but has a
rapid onset and short-lasting hypoglycemic effect as compared with the latter.
Mitiglinide has been synthesized by several related methods that involve
optical resolution,[2] asymmetric synthesis,[2a,3] and diasteroselective alky-
lation using chiral auxiliary.[4]
In a previous article,[2] two optical resolution methods of the key
compound racemic acid 4 were reported. One of them involves esterification
with optically active alcohols, which are separated into the diastereomers by
column chromatogeaphy and hydrolyzed. Only the diastereomeric (S)-N-
benzyl mandelamide ester could be separated; the overall yield was 28%,
Received in Japan September 20, 2006
Address correspondence to Wei Huang, Department of Chemistry, Shanghai
Institute of Pharmaceutical Industry, Shanghai 200437, China. E-mail: mrhwei@
hotmail.com
2153

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W. Huang and J.-D. Cen
Scheme 1.
and the optical purity of (S)-acid 6 was 92% ee. The alternative method was
optical resolution by optically active bases. The best result was 30.8% yield
and 97% ee when using (R)-1-(1-naphthyl)-ethylamine as a base. In this
article, we have developed a new optical resolution method of racemic ester 5
by a-chymotrypsin in 45.3% yield; the optical purity of (S)-acid (6) determined
by chiral-phase high performance liquid chromatography (HPLC) on Sumichiral
OA3300 was 99.2% ee, and, the method can be used for scale-up preparation.
The synthesis of free acid 6 is shown in Scheme 1. (3aR,7aS)-Octahydro-
2H-isoindole was chloroacetylated in the presence of Et3N to afford (3aR,
7aS)-2-(chloro-acetyl)-octahydro-2H-isoindole (2), which was condensed
with diethyl benzylmalonate followed by hydrolysis and decarbonylation to
obtain 4-[(3aR,7aS)-octahydro-2H-isoindol-2-yl]-4-oxo-2-benzyl-butanoic
acid (4). The overall yield of the three-step synthesis was 62.9%. The
racemic acid (4) was esterified with SOCl2/EtOH to give the corresponding
racemic ester (5). The (R)-ester was selectively hydrolyzed by a-chymotryp-
sin to separate out the (S)-ester, which was subjected to hydrolysis, giving 6.
The overall yield was 28.5% [based on (3aR,7aS)-octahydro-2H-isoindole].
Compound 6 was treated with calcium chloride and 25% ammonium
hydroxide to give mitiglinide; after recrystallization from 95% EtOH, the
pure product was obtained in 90% yield.
EXPERIMENTAL
All melting points are uncorrected. 1H NMR data were recorded on an Inova-
400 spectrometer in CDCl3 or DMSO-d6 using TMS as an internal standard.
Mass spectra were performed on Micro Mass Q-Tof Micro MS. Optical
rotation were measured on a WZZ-2A automatic polarimeter.

Novel Convenient Synthesis of Mitiglinide
2155
Step A: (3aR,7aS)-2-(Chloroacetyl)-octahydro-2H-isoindole (2)
Et3N (44.8 ml, 0.319 mol) was added to a solution of chloroacetyl
chloride (12.4 ml, 0.155 mol) and (3aR,7aS)-octahydro-2H-isoindole
(19.3 g, 0.154 mol) in CH2Cl2 (180 ml) below 108C. After the addition
was complete, the reaction mixture was stirred at room temperature
for 2 h. Then CH2Cl2 was removed under vacuum, and EtOAc (100 ml)
was added into the residue. It was washed with brine and dried over
anhydrous magnesium sulfate. The solution was concentrated to yield
27.5 g of 2 as oil, which was used directly in the next step. 1H NMR
(CDCl3, 400 M) d: 1.3–1.7 (8H, m), 2.1–2.3 (2H, m), 3.3–3.6 (4H, m),
3.97 (2H, s).
Step B: Ethyl 4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-
benzyl-2-carbethoxy-butanoate (3)
Sodium ethoxide was prepared by adding sodium (3.0 g, 0.13 mol) to EtOH
(90 ml), and after EtOH was removed under vacuum, EtOAc (100 ml) and
diethyl benzylmonate (31 g, 0.124 mol) were added into the residue. The
mixture was refluxed for 1 h. Then a solution of 2 from step A in EtOAc
(80 ml) was added dropwise refluxed for 3 h, cooled to room temperature,
washed with water, and dried over anhydrous magnesium sulfate. The
solution was concentrated to yield 27.5 g of 3 as oil, which was used
directly in the next step.
Step C: 4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-benzyl-
butanoic Acid (4)
To a solution of 3 from step B in EtOH (200 ml), aqueous NaOH (20%,
200 ml) was added. The mixture was stirred for 24 h; the EtOH was
removed under vacuum, adjusted to pH 1–2 with concentrated hydrochloric
acid, extracted with EtOAc, washed with brine, and dried over anhydrous
magnesium sulfate. The mixture was refluxed for 2 h. After EtOAc was
removed under vacuum, the residual solid was recrystallized from EtOAc/
petroleum ether to yield 25.4 g of 4 as a white solid. Mp 130–1348C (lit.
124–1258C[2a]).
Step D: Ethyl 4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-
benzyl-butanoate (5)
To a solution of 4 (24.7 g, 78.3 mmol) from step C in EtOH (200 ml), SOCl2
(6.8 ml) was added dropwise at 0–108C. After addition was completed, the

2156
W. Huang and J.-D. Cen
mixture was refluxed for 2 h. Then EtOH was removed under vacuum, and
EtOAc (100 ml) was added into the residue; washed successively with
brine, 5% NaHCO3, and brine; and dried over anhydrous magnesium
sulfate. The solution was concentrated to yield 28.3 g of 5 as oil, which was
used directly in the next step.
Step E: (2S)-4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-
benzyl-butanoic Acid (6)
Compound 5 from step D was suspended in water (500 ml). After a-chymo-
trypsin (6.2 g) was added, the mixture was stirred for 2 d at 32–338C, main-
taining pH at 7.2 by adding 1N NaOH. The mixture was extracted with ether,
washed with brine, and dried over anhydrous magnesium sulfate. After the
ether was removed under vacuum, EtOH (150 ml) and 1N NaOH (150 ml)
were added. The mixture was stirred for 24 h at room temperature. The
EtOH was removed under vacuum, washed with ether, adjusted to pH 1–2
with concentrated hydrochloric acid, extracted with ether, washed with
brine, and dried over anhydrous magnesium sulfate. The solution was concen-
trated to yield 11.2 g (45.3%) of 6 as oil.
Step F: Calcium Bis[(2S)-4-[(3aR,7aS)-octahydro-2H-isoindol-2-yl]-
4-oxo-2-benzyl-butanoate]dehydrate (Mitiglinide)
To 6 (23 g, 72.9 mmol) in EtOH (100 ml), a solution of CaCl2 (7.5 g) in water
(100 ml) and ammonium hydroxide (25–28%, 10 ml) was added. It was
stirred for 30 min at 808C, cooled to room temperature slowly, and then
stirred for 30 min at 08C. The slurry was filtered, and the cake was washed
with cool EtOH/H2O (1:1). The solid was recrystallized from 95% EtOH to
yield mitiglinide (22 g, 90%) as colorless crystals. Mp 175–1838C (lit.
1
179–1858C[2a]). [a]D20 ¼ þ5.5 (C1 MeOH) (lit. [a]1D8 ¼ þ5.7[2b]). H NMR
(DMSO-d6, 400M) d: 1.1–1.5 (16H, m), 2.0–2.3 (6H, m), 2.5–3.5 (20H,
m), 7.1–7.3 (10H, m); ESI-MS (m/z): 669 ([M-2H2O þ H]þ).
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