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1. A process for the production of bivalirudin of formula
H-D-Phe1-Pro-Arg-Pro-Gly5-Gly-Gly-Gly-Asn-Gly10-Asp-Phe-Glu-Glu-Ile15-Pro-Glu-Glu-Tyr-Leu20-OH (SEQ ID NO: 1) (I) comprising the steps of: (a) reacting an optionally side chain-protected peptide of formula
P1-D-Phe1-Pro-Arg-Pro-OH (SEQ ID NO: 4) (V), wherein P1 is a protecting group being stable to catalytic hydrogenation, with an optionally side chain-protected peptide of formula
H-Gly5-Gly-Gly-Gly-Asn-Gly10-OP2 (SEQ ID NO: 5) (VI), wherein P2 is a protecting group being removable by catalytic hydrogenation and being orthogonal to the optional side chain protecting group(s), to produce an optionally side chain-protected peptide of formula
P1-D-Phe1-Pro-Arg-Pro-Gly5-Gly-Gly-Gly-Asn-Gly10-OP2 (SEQ ID NO: 2) (VII), wherein P1 and P2 are as defined above, (b) removing P2 of the peptide produced in step (a) to produce the optionally side chain-protected peptide of formula
P1-D-Phe1-Pro-Arg-Pro-Gly5-Gly-Gly-Gly-Asn-Gly10-OH (SEQ ID NO: 2) (II), wherein P1 is as defined above, (c) reacting a side chain-protected peptide of formula
H-Glu-Glu-Ile15-Pro-Glu-Glu-Tyr-Leu20-OP3 (SEQ ID NO: 8) (X), wherein P3 is a protecting group being removable by catalytic hydrogenation, with a phenylalanine of formula
P4-Phe12-OH (XI), wherein P4 is a protecting group being orthogonal to the side chain protecting group(s) of the peptide of formula X and to P3, to produce a side chain-protected peptide of formula
P4-Phe-Glu-Glu-Ile15-Pro-Glu-Glu-Tyr-Leu20-OP3 (SEQ ID NO: 9) (XII), wherein P3 and P4 are as defined above, (d) removing P4 of the peptide produced in step (c) to produce the corresponding N-terminally deprotected, side chain protected peptide of formula XII, (e) reacting the peptide of formula XII produced in step (d) with a side chain protected aspartic acid of formula
P5-Asp11-OH (XIII), wherein P5 is a protecting group being orthogonal to the side chain protecting group(s) of the peptide of formula XII, to the side chain protecting group of the amino acid of formula XIII, and to the protecting group P3, to produce a side chain-protected peptide of formula
P5-Asp-Phe-Glu-Glu-Ile15-Pro-Glu-Glu-Tyr-Leu20-OP3 (SEQ ID NO: 3) (XIV), wherein P3 and P5 are as defined above, (f) removing P5 of the peptide produced in step (e) to produce the side chain-protected peptide of formula
H-Asp-Phe-Glu-Glu-Ile15-Pro-Glu-Glu-Tyr-Leu20-OP3 (SEQ ID NO: 3) (III), wherein P3 is as defined above, (g) reacting the optionally side chain-protected peptide of formula II produced in step (b) with the side chain-protected peptide of formula III produced in step (f) to produce a side chain-protected peptide of formula
P1-D-Phe1-Pro-Arg-Pro-Gly5-Gly-Gly-Gly-Asn-Gly10-Asp-Phe-Glu-Glu-Ile15-Pro-Glu-Glu-Tyr-Leu20-OP3 (SEQ ID NO: 1) (IV), wherein P1 and P3 are as defined above, (h) removing P1, P3 and the side chain protecting groups of the peptide produced in step (g) to produce bivalirudin of formula I, and wherein steps (a) through (g) are performed in solution phase. |
