Process for manufacturing macrocyclic peptides

Patent metadata

Field	Value
Publication number	US-2025109166-A1
Application number	US-202418803333-A
Country	US
Kind code	A1
Filing date	Aug 13, 2024
Priority date	Feb 14, 2022
Publication date	Apr 3, 2025
Grant date	—

Abstract

The invention provides a novel process for manufacturing a compound of formula (I), or a salt thereof,

wherein PG 1 , PG 2 and PG 3 are amino protective groups. The process according to the invention is particularly suitable for large-scale manufacturing under GMP conditions.

First claim

1 . A process for manufacturing a compound of formula (I), or a salt thereof,

comprising:
(a) reacting a carboxylic acid of formula (II)

with a secondary amine of formula (III)

using reagents selected from:
(i) HOAt and DIC;
(ii) HODhat and DIC;
(iii) HOPO and DIC;
(iv) HOPO and DCC; and
(v) HOPO and EDC;

to form a compound of formula (IV)

wherein PG 1 , PG 2 , PG 3 and PG 4 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc, and PG 5 is a carboxylic acid protective group selected from allyl and 9-fluorenylmethyl.

2 . The process according to claim 1 , wherein the process is performed in a solvent selected from:
(i) a mixture of tert-butyl methyl ether, n-heptane and dimethylacetamide; (ii) isopropylacetate with or without 1,3-dimethyl-2-imidazolidinone; (iii) tert-butyl methyl ether with or without 1,3-dimethyl-2-imidazolidinone; (iv) dichloromethane with or without 1,3-dimethyl-2-imidazolidinone; (v) THF with or without 1,3-dimethyl-2-imidazolidinone; (vi) 2-methyl-THF with or without 1,3-dimethyl-2-imidazolidinone; (vii) toluene with or without 1,3-dimethyl-2-imidazolidinone; and (viii) acetonitrile.

3 . The process according to claim 1 , further comprising:
(b1) reacting said compound of formula (IV), wherein PG 4 is Fmoc, with N-acetylcysteine and tAmNH 2 or tBuNH 2 , to form a compound of formula (V):

wherein PG 1 , PG 2 , and PG 3 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc, and PG 5 is a carboxylic acid protective group selected from allyl and 9-fluorenylmethyl; and
(b2) washing the reaction mixture obtained in (b1) with a basic aqueous solution.

4 . The process according to claim 3 , further comprising:
(c) reacting said compound of formula (V), with a compound of formula (VI):

wherein PG 6 is an amino protective group selected from BOC, Adoc, Moz, and Fmoc; in the presence of (i) a reducing agent selected from NaBH 3 CN and NaBH(OAc) 3 ; and (ii) a carboxylic acid selected from acetic acid and propionic acid; to form a compound of formula (VII):

wherein PG 1 , PG 2 , PG 3 and PG 6 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc, and PG 5 is a carboxylic acid protective group selected from allyl and 9-fluorenylmethyl.

5 . The process according to claim 4 , further comprising:
(d) reacting said compound of formula (VII), wherein PG 5 is an allyl group, with a transition metal catalyst in the presence of a secondary amine, to form a compound of formula (IX):

wherein PG 1 , PG 2 and PG 3 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc.

6 . The process according to claim 5 , wherein the secondary amine is Et 2 NH and the transition metal catalyst is (PPh 3 ) 4 Pd.

7 . The process according to claim 5 , wherein step (d) is performed in acetonitrile and further comprises working up the reaction mixture obtained from step (d) by:
(d2) adding N-acetylcysteine to said reaction mixture obtained from step (d); (d3) adding Cy 2 NH to the reaction mixture obtained from step (d2); (d4) distilling off the secondary amine from step (d); and (d5) filtering the reaction mixture obtained from step (d4).

8 . The process according to claim 5 , further comprising:
(e) reacting said compound of formula (IX) with:
(i) a mixture of HOBt and EDCI;
(ii) a mixture of DIC and oxyma;
(iii) COMU;
(iv) 2,4,6-trichloro-1,3,5-triazine (TCT); or
(v) 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM);
to form a compound of formula (I).

9 . A compound of formula (II),

or a salt thereof, wherein PG 1 , PG 2 and PG 4 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc.

10 . A compound of formula (III),

or a salt thereof, wherein PG 3 is an amino protective group selected from BOC, Adoc, Moz, and Fmoc, and PG 5 is a carboxylic acid protective group selected from allyl and 9-fluorenylmethyl.

11 . A compound of formula (IV),

or a salt thereof, wherein PG 1 , PG 2 , PG 3 and PG 4 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc, and PG 5 is a carboxylic acid protective group selected from allyl and 9-fluorenylmethyl.

12 . A compound of formula (V),

or a salt thereof, wherein PG 1 , PG 2 and PG 3 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc, and PG 5 is a carboxylic acid protective group selected from allyl and 9-fluorenylmethyl.

13 . A compound of formula (VII),

or a salt thereof, wherein PG 1 , PG 2 , PG 3 and PG 6 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc, and PG 5 is a carboxylic acid protective group selected from allyl and 9-fluorenylmethyl.

14 . A compound of formula (VIII),

or a salt thereof, wherein PG 1 , PG 2 and PG 3 and PG 6 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc.

15 . A compound of formula (IX),

or a salt thereof, wherein PG 1 , PG 2 and PG 3 are amino protective groups independently selected from BOC, Adoc, Moz, and Fmoc.

16 . The process according to claim 1 , wherein PG 1 , PG 2 and PG 3 are each BOC; PG 4 is Fmoc; and PG 5 is allyl.

17 . The process according to claim 3 , wherein PG 1 , PG 2 and PG 3 are each BOC; and PG 5 is allyl.

18 . The process according to claim 4 , wherein PG 1 , PG 2 and PG 3 are each BOC; PG 5 is allyl; and PG 6 is Fmoc.

19 . The process according to claim 6 , wherein PG 1 , PG 2 and PG 3 are each BOC; and PG 6 is Fmoc.

20 . The process according to claim 7 , wherein PG 1 , PG 2 and PG 3 are each BOC.

21 . A compound, which is N-NBS-N-Me-Trp-OAll

Assignees

• Hoffmann La Roche

Inventors

• Adam Jean-Michel
• Bliss Fritz
• Dott Pascal Jean Claude
• Hoffmann-Emery Fabienne Roxane
• Larsson Ulf Göran
• Puentener Kurt

Classifications

• C07K1/1077

  by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D209/26

  with an acyl radical attached to the ring nitrogen atom · CPC title

• C07D209/20

  substituted additionally by nitrogen atoms, e.g. tryptophane · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title