Improved synthesis of N,N′-disuccinimidyl carbonate using α-pinene as acid scavenger

Article abstract of DOI:10.1080/00397910500281291

An improved synthesis of N,N′-disuccinimidyl carbonate (DSC) is described where α-pinene is utilized as an efficient scavenger of HCl liberated during the reaction of N-hydroxysuccinimide with triphosgene in THF. The α-pinene hydrochloride formed is soluble in THF and gives very pure DSC in good yields. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500281291

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Improved Synthesis of N,N′‐Disuccinimidyl
Carbonate using α‐Pinene as Acid Scavenger
Maddipati Prasad a , Shaik Nowshuddin a & M. N. A. Rao a
a Divis Laboratories Limited , Hyderabad, India
Published online: 20 Aug 2006.
To cite this article: Maddipati Prasad , Shaik Nowshuddin & M. N. A. Rao (2005) Improved Synthesis of
N,N′‐Disuccinimidyl Carbonate using α‐Pinene as Acid Scavenger, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:24, 3119-3121
To link to this article: http://dx.doi.org/10.1080/00397910500281291
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Synthetic Communicationsw, 35: 3119–3121, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500281291
Improved Synthesis of N,N0-Disuccinimidyl
Carbonate using a-Pinene
as Acid Scavenger
Maddipati Prasad, Shaik Nowshuddin, and M. N. A. Rao
Divis Laboratories Limited, Hyderabad, India
Abstract: An improved synthesis of N,N0-disuccinimidyl carbonate (DSC) is described
where a-pinene is utilized as an efficient scavenger of HCl liberated during the reaction
of N-hydroxysuccinimide with triphosgene in THF. The a-pinene hydrochloride
formed is soluble in THF and gives very pure DSC in good yields.
Keywords: Acid scavenger, N,N0-disuccinimidyl carbonate, a-pinene
N-Hydroxysuccinimide (HOSu) esters of carboxylic acids are widely used in
organic chemistry, especially in peptide synthesis, as reactive acylating
reagents.[1] HOSu esters of N-protected amino acids are commercially
available. HOSu esters have been used to acylate other nucleophiles such as
alcohols[2] and hydroxylamines.[3] These esters are generally prepared by
reacting carboxylic acids with N-hydroxysuccinimide (HOSu) using dicyclo-
hexylcarbodiimide (DCC).[4] The DCC method has many drawbacks.[5,6]
Besides, DCC is a skin sensitizer and many pilot-plant facilities avoid its
use.[7]
Another convenient and preferred method for the preparation of hydroxy-
succinimidyl esters is by using N,N0-disuccinimidyl carbonate (DSC).[8,9]
Reaction of carboxylic acid with DSC in the presence of a base results in
Received in India April 7, 2005
Address correspondence to M. N. A. Rao, Divis Laboratories Limited, C-26,
Sanathnagar, Hyderabad 500018, India. Tel.: þ91-40-23704657; Fax: þ91-40-
23733242; E-mail: mnarao@divislaboratories.com
3119

3120
M. Prasad, S. Nowshuddin, and M. N. A. Rao
optically pure N-hydroxysuccinimide esters in very high yields. The reaction
proceeds at room temperature and the end of the reaction could be clarified
with the generation of carbon dioxide gas. DSC is not a skin irritant, unlike
DCC. After the reaction, it decomposes easily into water-soluble HOSu and
carbon dioxide.[8] Generally, DSC is prepared by reacting HOSu with
phosgene in the presence of a base (Scheme 1). Ogura et al. first prepared
DSC by silylating HOSu, followed by reaction with phosgene in THF.[8] Tri-
methylsilyldiethylamine (TMS-DEA) and hexamethyldisilazane (HMDS)
were used for sillation of HOSu. These silylating agents also acted as bases
to scavenge HCl liberated during the reaction. Konakahara et al.[10]
prepared DSC without using any silylating agents. They reacted HOSu with
triphosgene in presence of diisopropylethyl amine in dichloromethane
followed by purification using THF. Another similar method was reported
where tributyl amine was used as a base.[11] The role of the amine is to
scavenge the HCl liberated during the reaction.
Simple amines cannot be used as scavengers of HCl. Primary and
secondary amines cannot be used because they react with triphosgene.[12]
Tertiary amines such as triethyl amine cannot be used because their hydro-
chloride salts are insoluble in organic solvents and it is difficult to seperate
the salts from DSC. Only complex and expensive teriary amines such as dii-
sopropylethyl amine,[10] and tributyl amine,[11] whose hydrochloride salts are
soluble in organic solvents, are used to obtain the pure product.
In this communication we describe the preparation of DSC where
a-pinene is used as the scavenger of the liberated HCl. Unsaturated hydrocar-
bons with at least one of the carbons completely substituted by alkyl groups
are good candidates for making addition reactions with HCl. a-Pinene is
one such compound, and it is inexpensive and easily available. It is an
excellent scavenger of HCl, and the resulting addition product is very
soluble in solvents such as THF in which DSC is insoluble. Refluxing a
solution of THF containing HOSu, triphosgene, and a-pinene, followed by
cooling and filtering, resulted in pure DSC in high yields. The DSC
prepared by the literature methods usually contains small amounts of
HOSu, which can be detected in 1H NMR (signal at 2.58 ppm.) and
13C NMR (signals at 25.3 and 172.5 ppm). DSC prepared using a-pinene
was found to be completely free from HOSu. Reaction in solvents such as
dichloromethane, EtOAc, dioxane, dimethylformamide, and so forth resulted
in a gummy material, whereas THF gave a fine, colorless solid. Refluxing
Scheme 1.

Improved Synthesis of N,N0-Disuccinimidyl Carbonate
3121
for less than 12 h at room temperature resulted in lower yields. Two equivalents
of a-pinene were required for optimum yields.
EXPERIMENTAL
A solution containing N-hydroxysuccinimide (5.0 g, 0.04 mol), triphosgene
(2.5 g, 0.012 mol), and a-pinene (11.8 g, 0.086 mol) in THF (50 mL) was
refluxed under nitrogen for 12 h. The reaction mixture was concentrated
under vacuum to a small volume and cooled in an ice bath for 30 min. The
resulting slurry was filtered, and the solids obtained were washed with cold
THF (2 ꢀ 10 mL). The solid obtained was dried under vacuum to obtain
4.21 g (76%) of DSC (mp: 209–2118C). 1H NMR (DMSO-d6): 2.85 (s,
8-H) ppm. 13C NMR (DMSO-d6): 25.5; 149.5; 169.2 ppm. Anal. calcd. for
C9H8N2O7: C, 42.20%; H, 3.15%; N, 10.94%. Found: C, 42.13%; H,
3.15%; N, 10.99%.
ACKNOWLEDGMENTS
We thank Murali K. Divi, chairman and managing director, Divis Laboratories
Limited, and P. Gundu Rao, director, for their encouragement.
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