Efficient synthesis of sivelestat sodium hydrate

Article abstract of DOI:10.1080/00397910801982373

An efficient and scaleable synthesis of sivelestat sodium hydrate has been developed. Copyright Taylor & Francis Group, LLC.

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Efficient Synthesis of Sivelestat Sodium
Hydrate
G. Bijukumar a , B. Maloyesh a , S. S. Sampat a , S. B. Bhirud a & A. Rajendra
a
a Chemical Process Research and Development , Research and Development
Centre, Macleods Pharmaceuticals Ltd. , Mumbai, India
Published online: 09 May 2008.
To cite this article: G. Bijukumar , B. Maloyesh , S. S. Sampat , S. B. Bhirud & A. Rajendra (2008) Efficient
Synthesis of Sivelestat Sodium Hydrate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:11, 1718-1724, DOI: 10.1080/00397910801982373
To link to this article: http://dx.doi.org/10.1080/00397910801982373
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Synthetic Communicationsw, 38: 1718–1724, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801982373
Efficient Synthesis of Sivelestat Sodium
Hydrate
G. Bijukumar, B. Maloyesh, S. S. Sampat, S. B. Bhirud,
and A. Rajendra
Chemical Process Research and Development, Research and
Development Centre, Macleods Pharmaceuticals Ltd., Mumbai, India
Abstract: An efficient and scaleable synthesis of sivelestat sodium hydrate has been
developed.
Keywords: Glycine ethyl ester, isatoic anhydride, pivaloyloxy benzene sulfonyl
chloride, trimethyl silyl chloride
INTRODUCTION
Sivelestat sodium hydrate (Ono-5046, ElaspolTM) is an injectable selective
inhibitor of human neutrophil elastase jointly developed by Lilly and Ono for
the treatment of acute lung injury associated with systemic inflammatory
response syndrome (SIRS). Treatment with this agent has been shown to
improve respiratory function, which facilitates the early removal of patients
from mechanical ventilation and which could reduce the development of
ventilator-associated pneumonia and patient stay in intensive care. A new appli-
cation of elastase inhibitors has been reported[1] in the preparation of antiwrinkle
cosmetic composition, which includes sivelestat. The antiwrinkle activity is
believed to be the result of effective elastase inhibition, reduced hydrolytic
Received August 30, 2007
Address correspondence to G. Bijukumar, Chemical Process Research and Devel-
opment, Research and Development Centre, Macleods Pharmaceuticals Ltd., G-2,
Mahakali Caves Road, ShantiNagar, Andheri (E), Mumbai 400 093, India. E-mail:
dbijuin@yahoo.co.in
1718

Sivelestat Sodium Hydrate
1719
Figure 1. Sivelestat sodium hydrate.
rate, and the increased content of elastin in derma cortex by the elastase
inhibitors.
Sivelestat sodium hydrate is chemically known as N-[2-[4-(pivaloyloxy)
phenylsulfonamido] benzoyl] glycine sodium salt tetrahydrate 1 (Fig. 1).
A synthesis of sivelestat sodium has been reported by Imaki et al.[2,3] The
synthesis has started from o-nitro benzoic acid 2. o-Nitro benzoic acid was
converted to o-Nitrobenzoyl chloride and treated with glycine benzyl ester 3
to get (2-amino benzoyl amino) glycine benzyl ester 5. Condensation of
4-(pivaloyloxy) benzene sulfonyl chloride 6 with (2-aminobenzoyl) glycine
benzyl ester 5 in pyridine furnished N-[2-[4-(pivaloyloxy) phenylsulfona-
mido] benzoyl] glycine benzyl ester 7, which on hydrogenation followed by
treatment with sodium hydroxide furnished sivelestat sodium 1 (Scheme 1).
Wakatsuka et al.[4] has reported the synthesis of sivelestat sodium 1 by con-
densing anthranillic acid 9 with 4-(pivaloyloxy) benzene sulfonyl chloride 6 to
get O-(p-pivaloyloxybenzenesulfonylamino)benzoic acid 8, which on further
reaction with trimethylsilyl glycine furnished sivelestat 10 (Scheme 2).
RESULTS AND DISCUSSION
A retrosyntheticanalysishasbeencarriedout, andweidentifiedisatoicanhydride
as the key starting material. The synthesis was designed to eliminate the catalytic
hydrogenation as well as the dissolving metal reduction reported in earlier
syntheses.
We started our synthesis from isatoic anhydride. Isatoic anhydride 11 was
treated with glycine ethyl ester hydrochloride to get (2-Aminobenzoylamino)
acetic acid ethyl ester 12. (2-Aminobenzoylamino) acetic acid ethyl ester was

1720
G. Bijukumar et al.
Scheme 1. (i) Thionyl chloride, glycine benzylester; (ii) Fe/HCl; (iii) pivaloyloxy-
benzene sulfonylchloride, sodium hydroxide; (iv) Pd-C/H2 gas; (v) sodium hydroxide.
reacted with 6 to furnish N-[2,4-(pivaloyloxy) phenylsulfonamido] benzoyl]
glycine ethyl ester 13. Lam et al.[5] reported that aryl pivaloates are highly
stable in comparison with alkanoate esters for hydrolysis. Based on this
finding, we tried to selectively hydrolyze the ethyl ester in the presence of
aryl pivaloate ester. Compound 13 was subjected to hydrolysis with
aqueous sodium hydroxide, but in our hands the hydrolysis was not found
to be selective, and mixtures of products such as sivelestat 10 and
2-(4-hydroxy benzenesulfonylamino)-benzoylamino) acetic acid 10ꢀ were
obtained (Scheme 3). Other milder bases such as sodium carbonate and
sodium bicarbonate were employed for the hydrolysis, and we found that
none of the reagents could selectively hydrolyze the ethyl ester in the
presence of aryl pivaloate ester.
Based on this result, we modified the route of synthesis. Isatoic
anhydride 11 was treated with glycine ethyl ester hydrochloride to get (2-
aminobenzoylamino) glycine ethyl ester 12, which on hydrolysis with
aqueous sodium hydroxide furnished (2-aminobenzoylamino) acetic acid
14. (2-Aminobenzoylamino) acetic acid was treated with 4-(pivaloyloxy)
benzene sulfonyl chloride 5 in the presence of trimethyl silyl chloride
to yield sivelestat. It is reported[3] that
5
on reaction with
Scheme 2. (i) Sodium hydroxide and (ii) a-picoline, trimethylsilyl glycine.

Sivelestat Sodium Hydrate
1721
Scheme 3. (i) Glycine ethyl ester, triethyl amine; (ii) pivaloyloxy benzene sulfonyl
chloride; (iii) aq. sodium hydroxide or aq. sodium carbonate or aq. sodium bicarbonate.
(2-Aminobenzoylamino) acetic acid 14 will react not only with an amino
group in 14 but also with the carboxyl group, because of the fairly weak
nucleophilicity of the amino group, leading to formation of impurities. To
avoid the formation of impurities, the carboxyl group in 14 was protected
in situ as a trimethylsilyl derivative and treated with pivaloyloxy benzene
sulfonyl chloride to get the sivelestat in sufficiently pure form (Scheme 4),
which was converted to sivelestat sodium 1. In short, an efficient synthesis
of sivelestat sodium has been developed.
Scheme 4. (i) Glycine ethyl ester, triethyl amine; (ii) aq. sodium hydroxide; (iii) tri-
methylsilyl chloride, pyridine, pivaloyloxy benzene sulfonyl chloride; (iv) aq. sodium
hydroxide.

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G. Bijukumar et al.
EXPERIMENTAL SECTION
General Procedures
All reagents were commercially obtained and used as received unless
otherwise noted. All nonaqueous reactions were performed in dry glassware
under an atmosphere of dry nitrogen. Organic solutions were concentrated
by rotary evaporation at ꢀ80.0 mm Hg at less than 60 8C except where
noted. Thin-layer chromatography (TLC) was performed on Merck
precoated silica-gel 60F254 plates. Visualization of the developed chromato-
gram was performed by fluorescence quenching or phosphomolybdic acid
stain or 50% sulfuric acid char. 1H NMR spectra were measured on a
Varian-Gemini 300-MHz spectrometer.
N-(2-Aminobenzoyl) Glycine Ethyl Ester (12)
Isatoic anhydride (250 g, 1.53 mol) was added to a solution of glycine ethyl
ester hydrochloride (213.9 g, 1.53 mol) and triethylamine (162.8 g,
1.61 mol) in acetonitrile (1.25 L). The reaction mass was heated under
reflux for 3 h. After completion of the reaction (by TLC), the reaction
mass was concentrated under reduced pressure at 40–45 8C to get a
slurry. The slurry was dissolved in ethyl acetate (1.0 L) and washed with
water (2 ꢁ 1.0 L). The layers were separated, and the organic layer was con-
centrated to ꢀ400 ml to get a slurry, which was treated with n-hexane
(1.0 L) under stirring at 10–15 8C to separate the solids. The separated
solids were filtered and dried at 50–55 8C to get the title compound
(250 g, 73.4%). Melting point: 78–81 8C; IR (KBr) (ncm21): 3436, 3355,
2985, 1735, 1639, 1577, 1539, 1450, 1404, 1377, 1265, 1218, 1164,
1
1029, 995, 867, 744; H NMR (CDCl3) (d ppm): 7.43 (1H, q), 7.24 (1H,
m), 6.66 (2H, m), 6.60 (1H, bs), 5.50 (2H, bs), 4.28 (2H, q), 4.19 (2H,
d), 1.31 (3H, t); MS (m/z): 223 [M þ 1].
N-(2-Aminobenzoyl) Glycine (14)
N-(2-Aminobenzoyl) glycine ethyl ester (250.0 g, 1.12 mol) was added to a
solution of sodium hydroxide (62.5 g, 1.56 mol) in 750.0 ml of water and
stirred for 30 min at 25–30 8C. After completion of the reaction (by
TLC), the reaction mass was washed with 2 ꢁ 100 ml of dichloromethane
and separated into layers. The aqueous layer was neutralized by acetic
acid (95.0 g). The clear solution was distilled under reduced pressure to
ꢀ400.0 ml at 50–55 8C to get slurry. Isopropanol (750 ml) was added to
the slurry, stirred at 0–5 8C for 30 min, and filtered. The solids were
dried at 50–55 8C to give the title compound (194.9 g, 89.31%). Melting

Sivelestat Sodium Hydrate
1723
point: 164 8C (dec); IR (KBr) (ncm21): 3413, 3328, 3282, 2981, 2349, 1720, 1643,
1527, 1400, 1303, 1245, 1157, 1037, 999, 933, 794, 752; 1H NMR (DMSO-D6)
(d ppm): 12.56 (1H, bs), 8.51 (1H, t), 7.52 (1H, q), 7.15 (1H, m), 6.7 (1H, d), 6.54
(1H, m), 6.44 (2H, bs), 3.85 (2H, t); MS (m/z): 193 [M 2 1].
P-Pivaloyloxybenzenesulfonyl Chloride (6)
Sodium salt of p-pivaloyloxybenzenesulfonic acid (250 g, 0.89 mol) was
charged to toluene (2.5 L), and 1.25 L of toluene was distilled out azeotropi-
cally at 110–115 8C. The resulting slurry was cooled to 0–5 8C, and phos-
phorus oxychloride (136.9 g, 0.89 mol) was added dropwise in 15 min. The
mixture was stirred at 0–5 8C until completion (TLC). After completion of
the reaction, 1.25 L of water were added to the reaction mass at 0–5 8C and
stirred for 15 min. The layers were separated, and the organic layer was
distilled off at 50–55 8C to get slurry, which was cooled to 0–5 8C and
treated with hexane (300 ml) to separate the solids. The solids were filtered
and dried to get the title compound. (210.0 g, 85.22%). Melting point: 83–
87 8C; IR (KBr) (ncm21): 2981, 2939, 2318, 1751, 1589, 1458, 1369, 1107,
1
894, 844; H NMR (CDCl3) (d ppm): 1.37 (s, 9H), 7.34 (dd, 2H), 8.07 (dd,
2H); MS (m/z): 193 [M 2 1].
N-[O-(P-Pivaloyloxybenzenesulfonyl Amino) Benzoyl] Glycine (5)
Trimethylsilyl chloride (182.5 g, 1.6 mol) was added to a slurry of N-(2-
Aminobenzoyl) glycine (250 g, 1.28 mol) in pyridine (306.25 g, 3.87 mol)
and methylene chloride (1.25 L) dropwise at 25–30 8C, and the reaction
mass was stirred for 15 min. A solution of p-pivaloyloxy benzenesulfonyl
chloride (356.25 g, 1.27 mol) in dichloromethane (1.0 L) was added
dropwise to the reaction mass at 25–30 8C in 30 min. The reaction was
monitored by TLC. Upon completion of the reaction, the reaction mass
was distilled under reduced pressure to get a slurry. The slurry was
treated with 500.0 ml of water and extracted with dichloromethane
(2 ꢁ 500 ml). The layers were separated, and the organic layer was
washed with 10.0% HCl solution. The organic layers were further washed
with water (250.0 ml) and distilled under reduced pressure to ꢀ500.0 ml
to get slurry. The slurry was treated with ethyl acetate (200.0 ml) and
stirred at 10–15 8C for an hour and filtered to get the title compound
(391.5 g, 70.0%). Melting point: 213–217 8C; IR (KBr) (ncm21): 2977,
1747, 1720, 1693, 1519, 1454, 1334, 1103, 925, 759; 1H NMR
(CDCl3 þ DMSO-D6) (d ppm): 1.23 (9H, s), 3.87 (2H, d), 7.01 (1H, t),
7.10 (2H, d), 7.33 (1H, t), 7.52 (1H, d), 7.64 (1H, d), 7.74 (2H, d), 8.87
(1H, t), 11.39 (1H, s); MS (m/z): 434 [M].

1724
G. Bijukumar et al.
Sivelestat Sodium Hydrate (1)
N-[O-(P-Pivaloyloxybenzenesulfonyl amino) benzoyl] glycine (250.0 g,
0.57 mol) was dissolved in tetrahydro furan (THF) (1.0 L L). The solution
was cooled to 0–5 8C, and 5N aqueous solution of sodium hydroxide
(121.0 ml) was added and stirred for 30 min. The solvents were concentrated
under reduced pressure to 400.0 ml to get slurry, which was recrystallised
from water (750.0 ml). The solids were filtered and dried under reduced
pressure at 25–30 8C to obtain the product as white solid (243.5 gm, 80%).
Melting point: 104–108 8C; IR (cm21): v 3498, 3440, 2977, 2873, 1755,
1504, 1446, 1392, 1110, 941, 752; 1H NMR (DMSO-d6) (d ppm): 1.26
(s, 9H), 3.91 (s, 2H), 6.65 (t, 1H), 7.10 (m, 3H), 7.23 (d, 1H), 7.81 (m, 3H),
10.12 (s, 1H).
REFERENCES
1. Fleming, L. New use of elastase inhihitor. File date, September 15, 2005; WO
Patent 2005084612.
2. Imaki, K.; Arai, Y.; Okegawa, T. Derivatives of para substituted phenyl ester of
pivalic acid; File date, May 21, 1991. US Patent 5017610.
3. Imaki, K.; Wakatsuka, H. Glycine derivative monosodium salt tetrahydrate; File
date Oct 25, 1994. US Patent 5359121.
4. Wakatsuka, H.; Imaki, K.; Okada, T. Production of Glycine derivative; File date Feb
10, 1997. JP Patent 9040692.
5. Lam, L. K. T.; Farhat, T. Synthesis of 6-methoxy-1-oxaspiro[4,5]deca-6,9-diene-8-
one. Org. Prep. Proced. Int. 1978, 10, 79.