US 11,673,912 B2
Continuous, solvent-free and non-enzymatic peptide synthesis by reactive extrusion
Yves Yeboue, Montpellier (FR); Benjamin Gallard, Sarcelles (FR); Nicolas Le Moigne, Saint Sebastien d'Aigrefeuille (FR); Frédéric Lamaty, Montpellier (FR); Jean Martinez, Caux (FR); and Thomas-Xavier Metro, Montpellier (FR)
Assigned to CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE, Paris (FR); UNIVERSITE DE MONTPELLIER, Montpellier (FR); ECOLE NATIONALE SUPERIEURE DE CHIMIE DE MONTPELLIER, Montpellier (FR); ECOLE DES MINES D'ALES, Ales (FR); and ASSOCIATION POUR LA RECHERCHE ET LE DEVELOPPEMENT DES METHODES ET PROCESSUS INDUSTRIELS, Paris (FR)
Appl. No. 16/970,435
Filed by CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE, Paris (FR); UNIVERSITE DE MONTPELLIER, Montpellier (FR); ECOLE NATIONALE SUPERIEURE DE CHIMIE DE MONTPELLIER, Montpellier (FR); ECOLE DES MINES D'ALES, Ales (FR); and ASSOCIATION POUR LA RECHERCHE ET LE DEVELOPPEMENT DES METHODES ET PROCESSUS INDUSTRIELS, Paris (FR)
PCT Filed Feb. 12, 2019, PCT No. PCT/EP2019/053389
§ 371(c)(1), (2) Date Aug. 17, 2020,
PCT Pub. No. WO2019/158506, PCT Pub. Date Aug. 22, 2019.
Claims priority of application No. 18305160.6 (FR), filed on Feb. 16, 2018.
Prior Publication US 2021/0115085 A1, Apr. 22, 2021
Int. Cl. C07K 1/06 (2006.01); B29C 48/395 (2019.01); B29C 48/40 (2019.01)
CPC C07K 1/061 (2013.01) [B29C 48/397 (2019.02); B29C 48/40 (2019.02); B29K 2089/00 (2013.01)] 19 Claims
 
1. A continuous solvent-free and non-enzymatic method for synthesizing a compound of formula (I):
Ra-POLYPEP-Rc  (I)
wherein:
POLYPEP is a poly-amino acid compound,
Ra means a N-protective group;
Rc means-O-Rd, wherein Rd means a hydrogen atom, a (C1-C24 alkyl) group, a methyl group substituted with one or more phenyl groups, a non-substituted (C6-C10) aryl group, a O-protective group or a —NReRf group wherein Re and Rf groups mean, one independently of each other, a hydrogen atom, a (C1-C24) alkyl group, a methyl group substituted with one or more phenyl groups, a non-substituted (C6-C10 aryl) group or a N-protective group,
which method comprises the steps of:
a) feeding an extrusion reactor with
(1) a compound of formula (II)
Ra-PEPNt-Rg  (II)
wherein;
PEPNt is a mono- or a poly-amino acid compound,
Ra is as defined for the compound of formula (I), and
Rg is a leaving group
and
(2) a compound of formula (III)
H-PEPCt-Rc  (III)
wherein:
PEPCt is a mono- or a poly-amino acid compound, and
Rc is as defined for the compound of formula (I)
in the absence of any solvent,
so that the compound of formula (II) and the compound of formula (III) react together for generating a compound of formula (I), and
b) collecting the compound of formula (I) from the extrusion reactor, wherein:
at least one of the compound of formula (II) and the compound of formula (III) is provided in the form of a solution containing a liquid additive, and the step (a) does not include adding a separate liquid additive, wherein an appropriate viscosity of a mixture of the compound of formula (II) and the compound of formula (III) is reached by the liquid additive contained in the solution, or
both the compound of formula (II) and the compound of formula (III) are provided in solid form, and the step (a) further comprises adding a separate liquid additive to reduce a viscosity of a mixture of the compound of formula (II) and the compound of formula (III).