N , N ′ -disuccinimidyl carbonate

Structural formula
General
Surname	N , N ′ -disuccinimidyl carbonate
other names	Di ( N , N ′ -succinimidyl) carbonate; 1,1 '- [carbonyl bis (oxy)] dipyrrolidine-2,5-dione; Bis (2,5-dioxopyrrolidin-1-yl) carbonate; DSC;
Molecular formula	C 9 H 8 N 2 O 7
Brief description	white to beige crystal powder
External identifiers / databases
EC number	277-730-3
ECHA InfoCard	100.070.643
PubChem	676246
Wikidata	Q72469948
properties
Molar mass	256.17 g mol −1
Physical state	firmly
density	1.4274 g cm −3 at 20 ° C
Melting point	188-191 ° C ; 198-201 ° C ; 215 ° C ; 218-220 ° C ;
solubility	practically insoluble in water, soluble in acetonitrile and numerous organic solvents
safety instructions
GHS labeling of hazardous substances Caution
H and P phrases	H: 315-319-335
	P: 302 + 352-305 + 351 + 338
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

N , N ′ -Disuccinimidyl carbonate ( DSC ) is formally a carbonic acid ester with N -hydroxysuccinimide (NHS, a good leaving group ) and can therefore be regarded as “activated carbonic acid ”. Like the similar carbonyldiimidazole CDI, DSC is a synthesis equivalent of phosgene and is used for the preparation of so-called active esters in peptide chemistry . The activated carbonyl group of the N , N '-disuccinimidyl carbonate can be used preparatively for the construction of carbamates , ureas and heterocycles .

Manufacturing

The synthesis of N , N '-disuccinimidyl carbonate was described in 1979, starting from (A) N -hydroxysuccinimide (NHS) and diphosgene in xylene under reflux or (B) from trimethylsilylated NHS and phosgene in THF at 0 ° C.

Purification is carried out by recrystallization with acetonitrile.

In larger batches, DSC can be obtained in high purity without recrystallization in 89% yield with the more manageable phosgene substitute triphosgene in THF and the base tributylamine - whose hydrochloride is THF-soluble.

DSC produced in this way only contains traces of N -hydroxysuccinimide.

properties

N , N ′ -Disuccinimidyl carbonate is a white solid that crystallizes in prisms and is very slightly soluble in water, but readily soluble in organic solvents, especially acetonitrile. The widely scattering melting points are essentially due to impurities with the starting material N -hydroxysuccinimide.

Applications

With alcohols, N , N ′ disuccinimidyl carbonate forms the so-called “mixed carbonates”, which react with amines in a stoichiometric ratio to form carbamates .

Even with hindered alcohols, such as a substituted neopentyl alcohol , and hindered amino acids , such as tert- leucine , very high yields are achieved with low racemization .

A frequently used application of activating alcohols - described by Meir Wilchek - is the conversion of polyethylene glycols PEG or monomethylated m-PEG by means of DSC, which are used in the so-called PEGylation of proteins, in particular antibodies .

With excess amines, N , N ′ -Disuccinimidyl carbonate reacts via carbamates to form ureas .

The synthesis of particularly acid-labile N- carboxy anhydrides (NCA) , also known as Leuchs anhydrides , from z. B. amino acids blocked with the 9-xanthyl protective group on the amino function, proceeds with relatively high yields without racemization with N , N '-disuccinimidyl carbonate.

N , N '-Disuccinimidyl carbonate reacts with carboxylic acids in the presence of bases such as triethylamine or pyridine in acetonitrile at room temperature with evolution of CO ₂ to give N -hydroxysuccinimide esters, the so-called NHS active esters, in high yields .

Amino acids that carry a protective group on the amino group, such as. B. a Z group or Boc protecting group , form with DSC analogously NHS active esters without detectable racemization .

The reaction of these active esters with amino groups to form carboxamides is suitable for building up peptides and for linking functional carboxylic acids with proteins.

Individual evidence

↑ ^a ^b ^c ^d Data sheet di (N, N′-succinimidyl) carbonate for synthesis (PDF) from Merck , accessed on December 2, 2019.
^ Carl L. Yaws: Thermophysical Properties of Chemicals and Hydrocarbons . 2nd ed. Elsevier Inc., Oxford, UK 2015, ISBN 978-0-323-28659-6 , pp. 179 .
↑ Entry on N, N′-Disuccinimidyl Carbonate at Toronto Research Chemicals , accessed on December 2, 2019 ( PDF ).
↑ ^a ^b Entry on Di (N-succinimidyl) Carbonate at TCI Europe, accessed on December 02, 2019.
↑ ^a ^b ^c D. Pereira, TT Hai, D. Nelson: A convenient large scale synthesis of N, N′-disuccinimidyl carbonate . In: Synthetic Communications . tape 28 , no. 21 , 1998, pp. 4019-4024 , doi : 10.1080 / 00397919808004962 .
↑ ^a ^b ^c ^d H. Ogura, T. Kobayashi, K. Shimizu, K. Kawabe, K. Takeda: A novel active ester synthesis reagent (N, N'-disuccinimidyl carbonate) . In: Tetrahedron Lett. tape 49 , 1979, pp. 4745-4746 , doi : 10.1016 / S0040-4039 (01) 86699-5 .
↑ EC Davison, AK Ghosh, N. Kumaragurubaran, DTJ Morris, J. Clayden: N, N′-Disuccinimidyl Carbonate . In: e-EROS Encyclopedia of Reagents for Organic Synthesis . 2018, doi : 10.1002 / 047084289X.rd469.pub3 .
^ AK Ghosh, SP McKee, WJ Thompson: N, N′-Disuccinimidyl Carbonate: A Useful Reagent for Alkoxycarbonylation of Amines . In: Tetrahedron Lett. tape 33 , no. 20 , 1992, pp. 2781-2784 , doi : 10.1016 / S0040-4039 (00) 78856-3 .
^ AK Ghosh, M. Brindisi: Organic Carbamates in Drug Design and Medicinal Chemistry . In: J. Med. Chem. Volume 58 , no. 7 , 2015, p. 2895-2940 , doi : 10.1021 / jm501371s .
↑ H. Li, CY. Chen, JB Padros: Highly efficient carbamate formation from alcohols and hindered amino acids or esters using N, N'-disuccinimidyl carbonate (DSC) . In: Synlett . tape 10 , 2011, p. 1454-1458 , doi : 10.1055 / s-0030-1260584 .
↑ T. Miron, M. Wilchek: A simplified method for the preparation of disuccinimidyl carbonate polyethylene glycol for coupling to proteins . In: Bioconjugate Chem. Volume 4 , no. 6 , 1993, pp. 568-569 , doi : 10.1021 / bc00024a022 .
↑ K. Takeda, H. Ogura: Studies on heterocyclic compounds. XLIII. Insertion reaction of carbonyl group using disuccinimido carbonate (DSC) . In: Synth. Commun. tape 12 , no. 3 , 1982, pp. 213-217 , doi : 10.1080 / 00397918208063680 .
↑ J. Halstrom, K. Kovács: N-protected N-carboxyanhydrides IX. Synthesis of N-aralkyl α-amino acid N-carboxyanhydrides by carbonyl insertion with bis (N-succinimidyl) carbonate . In: Acta Chem Scand. B40, 1986, p. 462-465 , doi : 10.3891 / acta.chem.scand.40b-0462 .
↑ M. Morpurgo, EA Bayer, M. Wilchek: N-hydroxysuccinimide carbonates and carbamates are useful reactive reagents for coupling ligands to lysine in proteins . In: J. Biochem. Biophys. Methods . tape 38 , no. 1 , 1999, p. 17-28 , doi : 10.1016 / S0165-022X (98) 00027-X .

[Sigma-1] Data sheet di (N, N′-succinimidyl) carbonate for synthesis (PDF) from Merck , accessed on December 2, 2019.

[Yaws-2] Carl L. Yaws: Thermophysical Properties of Chemicals and Hydrocarbons . 2nd ed. Elsevier Inc., Oxford, UK 2015, ISBN 978-0-323-28659-6 , pp. 179 .

[3] Entry on N, N′-Disuccinimidyl Carbonate at Toronto Research Chemicals , accessed on December 2, 2019 ( PDF ).

[TCI-4] Entry on Di (N-succinimidyl) Carbonate at TCI Europe, accessed on December 02, 2019.

[Pereira-5] D. Pereira, TT Hai, D. Nelson: A convenient large scale synthesis of N, N′-disuccinimidyl carbonate . In: Synthetic Communications . tape 28 , no. 21 , 1998, pp. 4019-4024 , doi : 10.1080 / 00397919808004962 .

[Ogura-6] H. Ogura, T. Kobayashi, K. Shimizu, K. Kawabe, K. Takeda: A novel active ester synthesis reagent (N, N'-disuccinimidyl carbonate) . In: Tetrahedron Lett. tape 49 , 1979, pp. 4745-4746 , doi : 10.1016 / S0040-4039 (01) 86699-5 .

[e-EROS-7] EC Davison, AK Ghosh, N. Kumaragurubaran, DTJ Morris, J. Clayden: N, N′-Disuccinimidyl Carbonate . In: e-EROS Encyclopedia of Reagents for Organic Synthesis . 2018, doi : 10.1002 / 047084289X.rd469.pub3 .

[8] AK Ghosh, SP McKee, WJ Thompson: N, N′-Disuccinimidyl Carbonate: A Useful Reagent for Alkoxycarbonylation of Amines . In: Tetrahedron Lett. tape 33 , no. 20 , 1992, pp. 2781-2784 , doi : 10.1016 / S0040-4039 (00) 78856-3 .

[9] AK Ghosh, M. Brindisi: Organic Carbamates in Drug Design and Medicinal Chemistry . In: J. Med. Chem. Volume 58 , no. 7 , 2015, p. 2895-2940 , doi : 10.1021 / jm501371s .

[10] H. Li, CY. Chen, JB Padros: Highly efficient carbamate formation from alcohols and hindered amino acids or esters using N, N'-disuccinimidyl carbonate (DSC) . In: Synlett . tape 10 , 2011, p. 1454-1458 , doi : 10.1055 / s-0030-1260584 .

[11] T. Miron, M. Wilchek: A simplified method for the preparation of disuccinimidyl carbonate polyethylene glycol for coupling to proteins . In: Bioconjugate Chem. Volume 4 , no. 6 , 1993, pp. 568-569 , doi : 10.1021 / bc00024a022 .

[12] K. Takeda, H. Ogura: Studies on heterocyclic compounds. XLIII. Insertion reaction of carbonyl group using disuccinimido carbonate (DSC) . In: Synth. Commun. tape 12 , no. 3 , 1982, pp. 213-217 , doi : 10.1080 / 00397918208063680 .

[13] J. Halstrom, K. Kovács: N-protected N-carboxyanhydrides IX. Synthesis of N-aralkyl α-amino acid N-carboxyanhydrides by carbonyl insertion with bis (N-succinimidyl) carbonate . In: Acta Chem Scand. B40, 1986, p. 462-465 , doi : 10.3891 / acta.chem.scand.40b-0462 .

[14] M. Morpurgo, EA Bayer, M. Wilchek: N-hydroxysuccinimide carbonates and carbamates are useful reactive reagents for coupling ligands to lysine in proteins . In: J. Biochem. Biophys. Methods . tape 38 , no. 1 , 1999, p. 17-28 , doi : 10.1016 / S0165-022X (98) 00027-X .