An effective and convenient method for the preparation of KAD-1229

Article abstract of DOI:10.1002/hlca.200490174

A new convenient method for the asymmetric synthesis of the potent hypoglycemic agent KAD-1229 was developed. The key step of this method is diasteroselective alkylation of 1 to give crude 2 (d.e. > 93%) in good yield with the easily available Oppolzer's

Full text of DOI:10.1002/hlca.200490174

Helvetica Chimica Acta Vol. 87 (2004)
1935
An Effective and Convenient Method for the Preparation of KAD-1229
by Jianchao Liu, Yushe Yang*, and Ruyun Ji*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, P. R. China
(phone: ‡‡ 86-21-50806600-3405 (Y. Y. ); fax: 86-21-50806786, e-mail: jiruyan@yahoo.com.cn (R. J.);
nestliu@yahoo.com.cn (J. L. )
A new convenient method for the asymmetric synthesis of the potent hypoglycemic agent KAD-1229 was
developed. The key step of this method is diasteroselective alkylation of 1 to give crude 2 (d.e. > 93%) in good
yield with the easily available Oppolzer×s camphorsultam as chiral auxiliary. The overall yield of the product was
57%.
Introduction.
KAD-1229 (Mitiglinide calcium dihydrate ˆ calcium bis{(2S)-4-
dihy-
[(3aR,7aS)-octahydro-2H-isoindol-2-yl]-4-oxo-2-(phenylmethyl)butanoate}
drate), a novel hypoglycemic agent with a chemical structure different from that of
the sulfonylureas, exhibits a more-rapid-onset but shorter-lived hypoglycemic effect
than the sulfonylureas. Like the sulfonylureas, KAD-1229 inhibits the ATP-sensitive
potassium channels in pancreatic b-cells and stimulates insulin release [1]. The
configuration of the stereogenic C-atom in the succinyl moiety is very important for the
activity of the compound, and the absolute (S)-configuration is necessary for insulin-
secretory effect. Recently, KAD-1229 has been in phase-III clinical trials in Japan, and
in phase-II clinical trials in Europe and the U.S.A. for the treatment of type-2 diabetes,
and is expected to be launched in near future. The synthesis of KAD-1229 has been
accomplished by several related methods that involve optical resolution [2],
asymmetric synthesis by means of Evans chiral enolate [2a], and asymmetric
hydrogenation with the chiral diphosphine complex of rhodium or ruthenium [3].
However, since the above methods have drawbacks that limit large-scale preparation,
we have developed a new effective and convenient method for the preparation of
KAD-1229.
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

1936
Helvetica Chimica Acta Vol. 87 (2004)
Results and Discussion. Oppolzer×s camphorsultams serve as efficient, versatile,
and practical chiral auxiliaries that are easy to prepare from inexpensive camphor. Both
enantiomers are currently commercially available in bulk quantities. A highly p-face-
selective alkylation of enolate followed by nondestructive removal of the auxiliary
affords a highly optically active carboxylic acid. The absolute configuration of the
product can easily be directed by a very facile operation, and the products can be
purified by crystallization. Recycling of the chiral auxiliary after removal is practical.
This method is suitable for scaleable manufacture of pharmaceutical grade KAD-1229.
The process for the preparation of KAD-1229 starts from (À)-camphorsultam
(ˆ(3aS)-8,8-dimethylhexahydro-3a,6-methano-2,1-benzisothiazole 2,2-dioxide), read-
ily available in 85% yield from (‡)-d-camphor [4]. Treatment of (À)-camphorsultam
with excess 3-phenylpropionyl chloride in the presence of NaH in toluene at room
temperature gave 1 in 91% yield (Scheme) [5]. An alternative procedure is to reflux
camphorsultam with 1.1 toca. 1.5 equiv. of 3-phenylpropionyl chloride in MeCN for 8
10 h [6]. The crude product, acylsultam 1, purified by recrystallization from EtOH/H2O
in 89% yield, was reacted with an equimolar amount of base to form the chiral enolate
in dry ice/EtOH bath, followed by C(a)-re-alkylation [7] with tert-butyl bromoacetate
to give 2. The choice of the organic base was very important: the reaction with BuLi,
lithium diisopropylamide (LDA), or NaHMD (sodium hexamethyldisilazane) gave 2
in 30 40%, 60%, or 90% yield, respectively, after recrystallization from MeOH.
Alkylation promoted by these bases tends to give products with high diastereoselec-
tivity, and the diastereoisomeric purity of crude product 2 was determined to be
> 93%. However, the reaction with NaHMDS as the base proceeded smoothly in high
yield. The tert-butyl ester 2 was cleaved with TFA (CF3COOH) in CH2Cl2 to give the
free acid 3 in 87% yield [8]. Acylation of (3aR,7aS)-octahydro-1H-isoindole with 3 by a
mixed anhydride method afforded 4 in 84% yield [9]. Compound 4 can be also
obtained in 85% yield via direct alkylation of 1 with (3aR,7aS)-2-(bromoacetyl)octa-
hydro-1H-isoindole; however, the yield of the (2-bromoacetyl)octahydro-1H-isoindole
prepared from 2-bromoacetyl bromide and cis-octahydro-1H-isoindole was only 40%.
Nondestructive cleavage of 4 by hydroperoxide-assisted saponification (LiOH, aq.
H2O2, THF, r.t.) regenerated the camphorsultam (96% recovered yield) and gave
mitiglinide (5) in 93% yield and high enantiomeric excess (> 99% by HPLC analysis of
the corresponding methyl ester) [7]. Product 5 was treated with 2n NaOH, followed by
treatment with CaCl2. Recrystallization from aqueous EtOH gave KAD-1229 in 91%
yield, with a melting point and specific rotation data identical to those in the literature
[2b].
Conclusions. We describe herein an effective and facile asymmetric synthesis of
KAD-1229 from Oppolzer×s camphorsultam with an asymmetric alkylation as the key
step. The overall yield of the six-step synthesis was 57%.
We thank Dr. X . X u(Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences) for
performing HLPC. This research was supported by Science & Technology Commission of the Shanghai
Municipality (Grant 02QMB1409).

Helvetica Chimica Acta Vol. 87 (2004)
1937
Scheme. Synthetic Route to KAD-1229 from (À)-Camphorsultam
a) 3-Phenylpropanoyl chloride, NaH, in toluene, r.t.; 91%; or in MeCN, reflux, 10 h; 89%. b) NaHMDS, tert-
i
butyl bromoacetate, HMPA, THF, À 78 to ca. 08, 16 h; 92%. c) TFA, CH2Cl2; 87%. d) NMM, ClCO2 Bu,
(3aR,7aS)-octahydro-1H-isoindole, CH2Cl2; 84%. e) LiOH, aq. THF, 30% H2O2; 93%. f) 2n NaOH, CaCl2,
H2O/EtOH; 91%. g) NaHMDS, (3aR,7aS)-2-(bromoacetyl)octahydro-1H-isoindole, HMPA, THF À 78 to
ca. 08, 16 h; 85%.
ExperimentalPart
THF was freshly distilled from Na metal/benzophenone ketyl. All other reagents and solvents were used as
received without further purification. M.p.: B¸chi apparatus, uncorrected. Optical rotations: Perkin-Elmer 241
polarimeter at the sodium-D line. 1H-NMR Spectra: Varian Mercury-400 spectrometer, 400 MHz, in CDCl3;
chemical shifts d in ppm (TMS as internal standard). MS: Finnigan MAT-95 spectrometer. Elemental analyses:
Vario EL instrument.
(3aS,6R,7aS)-Hexahydro-8,8-dimethyl-1-(3-phenylpropanoyl)-3H-3a,6-methano-2,1-benzisothiazole 2,2-
Dioxide (1). Method A: To a soln. of (À)-camphorsultam (2.20 g, 10.22 mmol) in MeCN (10 ml) under N2
was added 3-phenylpropionyl chloride (1.90 ml, 12.78 mmol), and the soln. was heated to reflux for 10 h. After
the soln. was cooled to ambient temp., the MeCN was removed in vacuo. The residue was dissolved in AcOEt
and the org. phase was washed with sat. Na2CO3 and sat. NaCl soln., dried (MgSO4), filtered, and concentrated
under reduced pressure. The crude product was recrystallized from MeOH (or AcOEt/hexane) to afford 1 as a
white solid (3.16 g, 89%).
Method B: Compound 1 was also obtained in 91% yield according to [5].
20
20
D
Data of 1: M.p. 146 1488 (lit. 153 1548 [5]). ‰aŠ ˆ À85.6 (c ˆ 1.0, CHCl3) (lit. ‰aŠ ˆ À78.9, c ˆ 1.14 [5]).
D
1H-NMR: 0.95 (s, 3 H); 1.08 (s, 3 H); 1.34 1.42 (m, 2 H); 1.85 1.90 (m, 3 H); 2.05 2.07 (m, 2 H); 2.97 3.07

1938
Helvetica Chimica Acta Vol. 87 (2004)
‡
(m, 4 H); 3.40 3.50 (m, 2 H); 3.84 3.88 (m, 1H); 7.17 7.30 ( m, 5 H). EI-MS: 347 (M ). Anal. calc. for
C19H25NO3S (347.47): C 65.68, H 7.25, N 4.03; found: C 65.80, H 7.06, N 4.00.
1,1-Dimethylethyl (3S)-4-[(3aS,6R,7aS)-8,8-Dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benziso-
thiozol-1(4H)-yl]-4-oxo-3-(phenylmethyl)butanoate (2). To a soln. of 1 (1.74 g, 5.00 mmol) in THF (15 ml) at
À 788 under N2 was added NaHMDS (5.50 ml of a 1m soln. in THF) dropwise over 5 min. The soln. was stirred at
À 788 for 0.5 h, and a soln. of tert-butyl bromoacetate (2.20 ml, 15.00 mmol) and hexamethylphosphoramide
(HMPA) (2.62 ml, 15.00 mmol) in THF (5 ml) was added dropwise over 10 min. After stirring at À 788 for 16 h,
the soln. was warmed to r.t. and stirred for 4 h. The reaction was quenched with sat. aq. NH4Cl soln. (20 ml), and
the mixture was extracted with ether (3 Â 15 ml). The combined org. phase was washed with brine, dried
(MgSO4), and concentrated in vacuo to give crude product (d.e. > 93%). Crystallization from MeOH gave 2 as
20
crystals (2.13 g, 92%). M.p. 128 1298. ‰aŠ ˆ À58.2 (c ˆ 1.0, MeOH). 1H-NMR: 0.95 (s, 3 H); 1.09 (s, 3 H); 1.37
D
(s, 9 H); 1.40 1.48 (m, 2 H); 1.85 2.16 (m, 3 H); 2.31 2.69 ( m, 2 H); 2.99 3.08 (m, 4 H); 3.30 3.63 (m, 3 H);
‡
3.85 3.94 (m, 1H); 7.20 7.29 ( m, 5 H). EI-MS: 461( M ). Anal. calc. for C25H35NO5S (461.61): C 65.05, H 7.64,
N 3.03; found: C 64.91, H 7.53, N 2.99.
(3S)-4-[(3aS,6R,7aS)-Tetrahydro-8,8-dimethyl-2,2-dioxido-3a,6-methano-2,1-benzthiazol-1(4H)-yl]-4-
oxo-3-(phenylmethyl)butanoic Acid (3). Compound 2 (2.40 g, 2.60 mmol) was dissolved in CH2Cl2 (10 ml) and
cooled to 08. CF3COOH (10 ml) was added, and the mixture was stirred overnight at r.t. The volatiles were
removed under reduced pressure and the residue dissolved in AcOEt (15 ml). The org. phase was washed with
5% NaHCO3 soln. and brine, dried, and evaporated to give 3 (1.88 g, 87%) in sufficient purity to be employed in
20
subsequent steps. M.p. 202 2048 (AcOEt/MeOH). ‰aŠ ˆ À99.1( c ˆ 1.0, MeOH). 1H-NMR: 0.96 (s, 3 H); 1.17
D
(s, 3 H); 1.32 1.44 (m, 2 H); 1.85 1.92 (m, 3 H); 2.00 2.09 (m, 2 H); 2.36 2.49 (m, 2 H); 2.80 2.87 (m, 1 H);
‡
3.37 3.63 (m, 4 H); 3.91 3.94 ( m, 1H); 7.19 7.31( m, 5 H). EI-MS: 405 (M ). Anal. calc. for C21H27NO5S
(405.51): C 62.20, H 6.71, N 3.45; found: C 62.32, H 6.65, N 3.38.
(3aS,6R,7aS)-8,8-Dimethyl-1-{(2S)-4-[(3aR,7aS)-octahydro-2H-isoindol-2-yl]-4-oxo-2-(phenylmethyl)bu-
tanoyl}hexahydro-3a,6-methano-2,1-benzisothiazole 2,2-Dioxide (4). To a soln. of 3 (1.60 g, 3.95 mmol) in anh.
i
THF (5 ml) were added 4-methylmorpholine (NMM; 0.57 ml, 5.14 mmol) and ClCO2 Bu (0.69 ml, 5.33 mmol)
sequentially at À 128. After 5 min, (3aR,7aS)-octahydro-1H-isoindole (0.67 g, 5.33 mmol) was added. After 1h,
the soln. was filtered and the filtrate concentrated. The residual oil was dissolved in AcOEt (20 ml) and washed
successively with 10% NaHSO4 and aq. NaHCO3 soln., and brine. The org. layer was dried (Na2SO4), filtered,
20
D
and evaporated. The residue was recrystallized from AcOEt to give 4 (1.70 g, 84%). M.p. 188 1908. ‰aŠ
ˆ
À59.4 (c ˆ 1.0, MeOH). 1H-NMR: 0.96 (s, 3 H); 1.25 (s, 3 H); 1.28 1.52 (m, 10 H); 1.85 1.95 (m, 3 H); 1.98
2.18 (m, 4 H); 2.30 2.35 (m, 1H); 2.52 2.72 ( m, 2 H); 2.96 3.08 (m, 2 H); 3.14 3.37 (m, 3 H); 3.42 3.57
‡
(m, 3 H); 3.99 4.01( m, 1H); 7.20 7.29 ( m, 5 H). EI-MS: 512 (M ). Anal. calc. for C29H40N2O4S (512.70): C
67.94, H 7.86, N 5.46; found: C 68.10, H 7.81, N 5.33.
Compound 4 could be also obtained in 85% yield for direct alkylation of
1 from (3aR,7aS)-2-
(bromoacetyl)octahydro-1H-isoindole. (This reagent was prepared by addition of a soln. of bromoacetyl
bromide (12.06 g in 20 ml MeCN) to a soln. of (3aR,7aS)-octahydro-1H-isoindole (7.51g in 80 ml MeCN) with
cooling at À 108 and stirring. After 3 h, the mixture was filtered, and the filtrate was worked up to give 5.91g
(40% yield) of (2-bromoacetyl)octahydro-1H-isoindole.)
(2S)-4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-(phenylmethyl)butanoic Acid (ˆ Mitiglinide, 5).
To a soln. of 4 (1.64 g, 3.20 mmol) in 25 ml THF/H2O 1:1were added aq. 30% H 2O2 (2.56 ml, 25.60 mmol) and
LiOH ¥ H2O (0.54 g, 12.80 mmol) at 08. The mixture was stirred at 08 for 1h and then at r.t. for 12 h. Dilution
with H2O, extraction with CH2Cl2, drying (MgSO4) of the org. phase, and evaporation regenerated the chiral
auxiliary camphorsultam. The aq. phase was acidified to pH 1 2 with 1n HCl, sat. with NaCl, and extracted with
AcOEt. Drying and evaporation of solvent afford mitiglinide (0.94 g, 93%) as a colorless viscous oil. The ee was
determined to be 99.4% by HPLC analysis of the corresponding Me ester on a Chiralcel AS column (250 Â
20
D
4.6 mm, flow rate 0.7 ml/min, UV 214 nm, n-hexane/i-PrOH 80 :20 as the eluent). ‰aŠ ˆ À3.5 (c ˆ 1.0, MeOH).
1H-NMR: 1.23 1.63 (m, 8 H); 2.13 2.22 (m, 2 H); 2.42 2.52 (m, 2 H); 2.73 3.32 (m, 7 H); 7.18 7.32
‡
(m, 5 H). ESI-MS: 316.15 ([M ‡ H] ). Anal. calc. for C19H25NO3 (315.41): C 72.35, H 7.99, N 4.44; found: C
72.51, H 8.03, N 4.31.
Calcium Bis{(2S)-4-[(3aR,7aS)-octahydro-2H-isoindol-2-yl]-4-oxo-2-(phenylmethyl)butanoate} Dihydrate
(KAD-1229). A soln. of mitiglinide (0.81g, 2.57 mmol) in EtOH (3 ml) was treated with 2 n NaOH soln.
(1.28 ml, 12.57 mmol). The mixture was evaporated under reduced pressure. The residue was dissolved in H2O
(6 ml), and a soln. of CaCl2 (1.51 g, 10.24 mmol) in H O (2 ml) was added, followed by vigorous stirring for 1h.
2
The mixture was extracted with CHCl3 (5 Â 4 ml), the org. layer was washed with H2O, dried (Na2SO4), and
evaporated under reduced pressure. The residue was recrystallized from 95% EtOH to give KAD-1229 as

Helvetica Chimica Acta Vol. 87 (2004)
1939
20
D
20
D
colorless crystals (0.82 g, 91%). M.p. 179 1858 (lit. 179 1858 [2b]). ‰aŠ ˆ ‡5.4 (c ˆ 0.6, MeOH) (lit. ‰aŠ
ˆ
‡5.7, c ˆ 1.0, MeOH [2b]). 1H-NMR: 1.13 1.39 (m, 16 H); 2.0 2.3 (m, 6 H); 2.54 2.83 (m, 14 H); 3.20 3.22
‡
(m, 6 H); 7.11 7.28 (m, 10 H). ESI-MS: 669.32 ([M À 2 H2O ‡ H] ). Anal. calc. for C38H48CaN2O6 ¥ 2 H2O
(704.91): C 64.75, H 7.44, N 3.94; found: C 64.46, H 7.35, N 3.73.
REFERENCES
[1] H. Ohnota, T. Koizumi, N. Tsutsumi, M. Kobayashi, S. Inoue, S. J. Sato, Pharmacol. Exp. Ther. 1994, 269,
489; H. Ohnota, M. Kobayashi, T. Kiozumi, K. Katsuno, F. Sato, T. Azisawa, Biochem. Pharmacol. 1995, 49,
165; M. Kinukawa, H. Ohnota, T. Azisawa, Br. J. Pharmacol. 1996, 117, 17021.
[2] a) T. Yamaguchi, T. Yanagi, H. Hokari, Y. Mukaiyama, T. Kamijo, I. Yamamoto, Chem. Pharm. Bull. 1997,
45, 1518; b) T. Yamaguchi, T. Yanagi, H. Hokari, Y. Mukaiyama, T. Kamijo, I. Yamamoto, Chem. Pharm.
Bull. 1998, 46, 337.
[3] J. P. Lecouve, C. Fugier, J. C. Souvie, Pat. WO9901430, 1999 (Chem. Abstr. 1999, 130, 110156r).
[4] M. Vandewalle, J. Van der Eycken, W. Oppolzer, C. Vullioud, Tetrahedron 1986, 42, 4035; F. A. Davis, J. C.
Towson, M. C. Weismiller, S. Lal, P. J. Carroll, J. Am. Chem. Soc. 1988, 110, 8477.
[5] W. Oppolzer, O. Tamura, J. Deerberg, Helv. Chim. Acta 1992, 75, 1965.
[6] M. C. William, B. Corey, J. Org. Chem. 1998, 63, 6732.
[7] W. Oppolzer, R. Moretti, S. Thomi, Tetrahedron Lett. 1989, 30, 5603.
[8] H. Heitsch, R. Henning, H. W. Kleemann, W. Linz, W. U. Nicke, D. Ruppert, H. Urbach, A. Wagner, J.
Med. Chem. 1993, 36, 2788.
[9] J. J. Plattner, P. A. Marcotte, H. D. Kleinert, H. H. Stein, J. Greer, G. Bolis, A. K. L. Fung, B. A. Bopp, J. R.
Luly, J. Med. Chem. 1988, 31, 2277.
Received March 17, 2004