Method for preparing FMOC-based hydrolysable linkers
View Patent ↗A novel process for the production of Fmoc (9H-fluoren-9-ylmethoxycarbonyl)-based compounds is provided, wherein a protecting group for the 9-hydroxymethyl group of the fluorene ring system is utilized. These compounds are useful for the modification of protein and peptide drugs.
1. A compound of the formula 1,
wherein PG is a silyl protecting group;
at least one of position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y; and
at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical X;
Y is
R 1 is independently a (C 1 -C 8 )-alkyl;
R 2 is selected from the group consisting of —C(O)NR—, —C(O)NR—(C 1 -C 8 )-alkyl-NR—, —NRC(O)— and —NRC(O)—(C 1 -C 8 )-alkyl-NR, and
R is independently hydrogen or C 1 -C 8 -alkyl;
X is —SO 3 —R 3 ;
R 3 is independently selected from the group consisting of hydrogen, (C 1 -C 8 )-alkyl and (C 1 -C 8 )-alkyl-R 4 ; and
R 4 is a polymer.
2. A method of preparing a compound according to formula 1:
wherein PG is a silyl protecting group and at least one of position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y;
Y is
R 1 is independently a (C 1 -C 8 )-alkyl, and
R 2 is selected from the group consisting of —C(O)NR—, —C(O)NR—, —(C 1 -C 8 )-alkyl-NR—, —NRC(O)— and —NRC(O)—(C 1 -C 8 )-alkyl-NR, and
R is independently hydrogen or C 1 -C 8 -alkyl; and
at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical X;
X is —SO 3 —R 3 ;
R 3 is independently selected from the group consisting of hydrogen, (C 1 -C 8 )-alkyl and (C 1 -C 8 )-alkyl-R 4 ; and
R 4 is a polymer;
said method comprises the step of reacting the 9-hydroxymethyl group of a compound of formula 2 to introduce PG:
wherein at least one of position 1, 2, 3, 4, 5, 6, 7, or 8 is bound to an amine,
and subsequently reacting the amine to introduce Y and form the compound of formula (1).
3. The method according to claim 2 , wherein said 9-hydroxymethyl group is reacted with a silyl halide.
4. The method according to claim 3 , wherein said silyl halide is tert-butyldimethylsilyl chloride (t-BDMS-Cl).
5. The method according to claim 4 , wherein said reaction with tBDMS-Cl is performed with imidazole in dimethylformamide.
6. The method according to claim 5 , wherein said amine is reacted with maleimidoalkylic acid.
7. The method according to claim 2 , wherein PG is tert-butyldimethylsilyl.
8. A method of preparing a compound according to formula 1:
wherein PG is a silyl protecting group;
at least one of position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y;
Y is:
R 1 is a (C 1 -C 8 )-alkyl;
R 2 is selected from the group consisting of —NRC(O)— and —NRC(O)—(C 1 -C 8 )-alkyl-NR—,
R is hydrogen or C 1 -C 8 -alkyl;
at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is optionally bound to radical X;
X is —SO 3 —R 3 ;
R 3 is selected from the group consisting of hydrogen, (C 1 -C 8 )-alkyl and (C 1 -C 8 )-alkyl-R 4 ; and
R 4 is a polymer;
said method comprising protecting a hydroxyl of a compound of formula (2) with a silyl protecting group to form an intermediate compound:
wherein at least one of position 1, 2, 3, 4, 5, 6, 7, or 8 of formula (2) is bound to an amine, and reacting the amine of the intermediate compound to provide radical Y and form the compound of formula (1).
9. The method of claim 8 , wherein at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical X.