FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. – “A process for the preparation of N,N'-Disuccinimidyl carbonate”
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the invention:
The present invention relates to a process for preparation of N,N'-Disuccinimidyl
carbonate (DSC) represented by a structural formula (I) as given below.

Background of the invention:
The molecular formula of DSC is N,N'-Disuccinimidyl carbonate (DSC) is C9H8N2O7 and molecular weight is 256.17. CAS registry No. of DSC is [74124-79-1].
DSC is used for the preparation of hydroxysuccinimidyl ester. N-Hydroxysuccinimide (HOSu) esters of carboxylic acids are widely used in organic chemistry, especially in peptide synthesis, as reactive acylating reagents.
Ogura et al. first prepared DSC by silylating N-Hydroxysuccinimide (HOSu) followed by reaction with phosgene in the presence of base in THF. The process is described in Tetrahedron Lett. 1979, 49, 4745-4746. Trimethylsilyldiethylamine (TMS-DEA) and hexamethyldisilazane (HMDS) were used for silylation of N-Hydroxysuccinimide (HOSu). These silylating agents acted as base to scavenge HC1 liberated. The synthetic scheme is as given below.

Konakahara et al. prepared DSC without using any silylating agent. The process is mentioned in Synthesis 1993, 103-106 in which HOSu is reacted with triphosgene in the presence of diisopropylethyl amine in dichloromethane followed by purification using THF.
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Another similar method was reported in Synth. Commun. 1998, 28, 4019-4024 in which tributyl amine was used as a base. The role of the amine is to scavenge the HC1 liberated during the reaction. The drawback of this process is that primary and secondary amines can not be used because they react with triphosgene. Tertiary amines such as triethyl amine cannot be used because their hydrochloride salts are insoluble in organic solvents and it is difficult to separate salts from DSC. Only complex and expensive tertiary amines such as diisopropyl amine and tributyl amine whose hydrochloride salts are soluble in organic solvents can be used to obtain the pure product.
One more process is reported for the preparation of DSC in Synth Commun. 2005, 35, 3119-3121 in which a-pinene is used as the scavenger of the liberated HC1. The HOSu is reacted with triphosgene in THF and in the presence of a-pinene.
Prior art relating to the process for the preparation of DSC suffers with several drawbacks such as preparation of reactive derivative via silylation step, low purity level due to presence of unreacted HOSu and use of expensive reagents which increases the overall cost of the production.
Hence, there is a need to develop a process which not only overcomes disadvantages of the prior art but also provide a process which is economical, operationally simple and industrially applicable.
Unexpectedly, present inventors have found that the reaction between HOSu and triphosgene can take place even without the use of an acid scavenger. Therefore, the present inventors provide a cost effective process in which the use of acid scavenger is completely eliminated.
The distinct advantage of this process is that the reaction is taking place without utilizing any acid scavenger.
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Object of the invention:
The primary object of the present invention is to provide a process for the preparation of DSC without using any acid scavenger.
Another object of the present invention is to provide a process which is economical and operationally simple.
A further object of the present invention is to provide a process which is easy to handle at an industrial scale.
Detailed description of the invention:
Accordingly, the present invention provides a process for preparation of DSC (N,N’-
Disuccinimidyl carbonate) of formula (I)

comprising a step of reacting N-Hydroxysuccinimide (HOSu) of formula (II)

with phosgene or any compound capable of liberating phosgene in the presence of an organic solvent without using acid scavenger.
The example of organic solvent includes but not limited to aromatic hydrocarbon such as toluene, xylene, benzene, 1,2,3-trimethylbenzene, chlorobenzene, anisole and the like or the mixture thereof. The most preferred organic solvent is Toluene.
The example of compound capable of liberating phosgene includes but not limited to triphosgene, diphosgene and the like or mixture thereof.
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The term "acid scavenger" as used hereinabove refers to any base or a compound, the presence of which in the reaction facilitates the neutralization or removal of HC1 produced.
Suitable acid scavengers include bases such as tributyl amine, triethylamine, diisopropylethylamine, diethylmethylamine, ethyl dimethyl amine, N-methylpyrrolidine, N-methylpiperidine and the like or mixture thereof. Suitable acid scavengers also include compounds having unsaturation which is capable of trapping the HC1 liberated in the reaction. The examples of such kind of scavengers are a-pinene, vinyl acetate, l,4,4a,5,8,8a-hexahydronaphthalene and the like.
The present invention eliminates the use of acid scavenger without compromising the quality and yield of the final product which makes the process not only economical but also operationally simple.
Phosgene or any compound capable of liberating phosgene is added to a solution of N-hydroxysuccinimide in toluene and heated to a temperature ranging from about 60°C to about 120°C. After completion of the reaction toluene is removed optionally under vacuum and the residue is stirred in with tetrahydrofuran at a temperature ranging from about 60° to about 65 C. The slurry was cooled in ice bath and isolated by the methods known in the art such as filtration, decantation or centrifugation. The solid is dried to give N,N'-Disuccinimidyl carbonate (DSC).
In a preferred embodiment of the present invention, the compound capable of liberating phosgene is triphosgene.
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.
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Exam pie-1
Preparation of N,N'-Disuccinimidyl carbonate (DSC)
Triphosgene (25g) was added to a solution of N-hydroxysuccinimide (50g) in Toluene
(250ml) under nitrogen atmosphere and stirred for 10 hours at 110° to 115°C. Toluene
was evaporated under vacuum and the residue was stirred with Tetrahydrofuran (100ml)
at 60° to 65°C for 30 min. The resulting slurry was cooled in ice bath for 2 hours and
filtered. The solid obtained was washed with cold Tetrahydrofuran (25ml X 2). The solid
was dried under nitrogen to obtain N,N'-Disuccinimidyl carbonate (39.60g).
(Yield: 72%)
Melting Point: 209-214°C
'H NMR (DMSO-d6): 2.84 (s, 8H) ppm
l3C NMR(DMSO-d6): 26.3; 150.2; 169.9 ppm
Example-2
Preparation of N,N'-Disuccinimidyl carbonate (DSC)
Triphosgene (12.5g) was added to a solution of N-hydroxysuccinimide (25g) in Xylene
(125ml) under nitrogen atmosphere and stirred for 10 hours at 110° to 115°C. Xylene was
evaporated under vacuum and the residue was stirred with Tetrahydrofuran (50ml) at 60°
to 65°C for 30 min. The resulting slurry was cooled in ice bath for 2 hours and filtered.
The solid obtained was washed with cold Tetrahydrofuran (12ml X 2). The solid was dried
under nitrogen to obtain N,N'-Disuccinimidyl carbonate (19.25g).
(Yield: 70%)
Melting Point: 208-211°C
'H NMR (DMSO-d6): 2.84 (s, 8H) ppm
l3C NMR (DMSO-d6): 26.3; 150.2; 169.9 ppm
Example-3
Preparation of N,N'-Disuccinimidyl carbonate (DSC)
Phosgene gas (51.6g) was dissolved in Toluene (250ml) under nitrogen atmosphere followed by addition of N-hydroxysuccinimide (50g). The reaction mixture was stirred for 10 hours at 110° to 115°C. Toluene was evaporated under vacuum and the residue
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was stirred with Tetrahydrofuran (100ml) at 60° to 65 C for 30 min. The resulting slurry was cooled in ice bath for 2 hours and filtered. The solid obtained was washed with cold Tetrahydrofuran (25ml X 2). The solid was dried under nitrogen to obtain of N,N'-Disuccinimidyl Carbonate (37.20g). (Yield: 67.5%)
Melting Point: 210-215°C
'H NMR (DMSO-d6): 2.84 (s, 8H) ppm
l3C NMR (DMSO-d6): 26.3; 150.2; 169.9 ppm
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What is claimed is:
1. A process for the preparation of N,N'-Disuccinimidyl carbonate (DSC) of formula
(I)

comprising a step of reacting N-Hydroxysuccinimide (HOSu) of formula (II)

with Phosgene or any compound capable of liberating phosgene in the presence of an organic solvent and in the absence of acid scavenger.
2. The process as claimed in claim 1, wherein an organic solvent is selected from the group comprising aromatic hydrocarbon.
3. The process as claimed in claim 2, wherein an organic solvent is selected from toluene, xylene, benzene, 1,2,3-trimethylbenzene, chlorobenzene, anisole or mixture thereof.
4. The process as claimed in claim 1, wherein compound capable of liberating phosgene is triphosgene.
5. A process for the preparation of N,N'-Disuccinimidyl carbonate (DSC) of formula
(I)

comprising a step of reacting N-Hydroxysuccinimide (HOSu) of formula (II)

with Phosgene or any compound capable of liberating phosgene in the presence of toluene and in the absence of acid scavanger.
6. The process as claimed in claim 5, wherein compound capable of liberating phosgene is triphosgene.
Dated this 22nd day of March 2006

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