Peptide production and purification process

1 . A process for the synthesis of a Gly-Gly-Val-Leu-Val-Gln-Pro-Gly octapeptide (SEQ ID NO 1) comprising at least one peptide coupling step carried out in solution.

2 . The process according to claim 1 , which comprises coupling a peptide of formula:

Val-Gln-Pro-Gly-Y (SEQ ID NO 2);

wherein the C-terminal amino acid is protected by a carboxylic acid protecting group Y, preferably selected from alkyl esters, aryl esters, aralkyl esters and silyl groups, more preferably a tert.butyl ester;

with a Leucine or a C-terminal Leucine peptide, preferably selected from formulae:

X-Gly-Gly-Val-Leu (SEQ ID NO 3), X-Gly-Val-Leu and X-Val-Leu;

wherein the N-terminal amino acid is protected by an amino protecting group X preferably selected from allyloxycarbonyl groups, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Z), 9-fluorenylmethyloxycarbonyl (Fmoc), 4-nitrobenzenesulfonyl (Nosyl), 2-nitrobenzenesulfenyl (Nps) and substituted derivatives, more preferably a tert-butyloxycarbonyl (BOC) group;

and wherein said Leucine or C-terminal Leucine peptide is optionally activated by a carboxylic acid activating agent.

3 . The process according to claim 2 , wherein the C-terminal Leucine peptide is X-Gly-Gly-Val-Leu (SEQ ID NO 3).

4 - 8 . (canceled)

9 . The process according to claim 1 , wherein after the coupling step, the solution is treated with an aqueous phase so as to provide a solution of coupled product in the aqueous phase and then, the coupled product is extracted from the aqueous phase into an organic solvent.

10 - 20 . (canceled)

21 . The process according to claim 1 , according to the scheme:

wherein X is an amino protecting group, and Y is a carboxyl protecting group.

22 . The process according to claim 1 , according to the scheme:

wherein X is an amino protecting group, and Y is a carboxyl protecting group.

23 - 56 . (canceled)

57 . The process according to claim 21 wherein all coupling steps are carried out in solution.

58 . The process according to claim 57 , wherein at least one intermediate peptide formed by coupling in solution or a Gly-Gly-Val-Leu-Val-Gln-Pro-Gly octapeptide (SEQ ID NO 1) is isolated and purified by an operation comprising at least one solid/liquid separation step selected from the group consisting of a precipitation and a crystallization.

59 . The process according to claim 58 , wherein the solid/liquid separation step is a precipitation, and wherein the precipitation is performed by the addition of a solution of the peptide in a first solvent to a second solvent wherein the peptide is less soluble than in the first solvent.

60 . The process according to claim 58 , wherein the solid/liquid separation step is a crystallization and wherein the crystallization is performed by the addition to a solution of the peptide in a first solvent of a second solvent wherein the peptide is less soluble than in the first solvent.

61 . The process according to claim 22 wherein all coupling steps are carried out in solution.

62 . The process according to claim 61 , wherein at least one intermediate peptide formed by coupling in solution or a Gly-Gly-Val-Leu-Val-Gln-Pro-Gly octapeptide (SEQ ID NO 1) is isolated and purified by an operation comprising at least one solid/liquid separation step selected from the group consisting of a precipitation and a crystallization.

63 . The process according to claim 62 , wherein the solid/liquid separation step is a precipitation, and wherein the precipitation is performed by the addition of a solution of the peptide in a first solvent to a second solvent wherein the peptide is less soluble than in the first solvent.

64 . The process according to claim 62 , wherein the solid/liquid separation step is a crystallization and wherein the crystallization is performed by the addition to a solution of the peptide in a first solvent of a second solvent wherein the peptide is less soluble than in the first solvent.

65 . Peptides of the formula

Glp-Pro-Gly,

Val-Gln-Pro-Gly,

(SEQ ID NO 2)

Leu-Val-Gln-Pro-Gly,

(SEQ ID NO 4)

Val-Leu-Val-Gln-Pro-Gly,

(SEQ ID NO 5)

Gly-Val-Leu-Val-Gln-Pro-Gly,

(SEQ ID NO 6)

or protected peptides of the formula

X-Glp-Pro-Gly,

X-Val-Gln-Pro-Gly,

(SEQ ID NO 2)

wherein X is an amino protecting group.