Process for preparing pharmaceutical compound and intermediates thereof
The present invention relates to novel intermediates of formula VII, or an acid addition salt or a solvate thereof, wherein R 1 is —(CO)NH 2 , —CH 2 NH 2 or —CN; R 2 =R 3 =H or R 2 and R 3 together form a cyclic boronate or borate ester; X is a helping group selected from the group consisting of i) a five or six membered heterocyclic aromatic ring and derivatives thereof comprising at least one N-atom being a part of an imine-group, wherein said N-atom forms the point of connection to the cyclohexapeptide ring, and ii) tetrazolyl and derivatives thereof for which a nitrogen atom forms the point of connection to the cyclohexapeptide ring, and a process for the preparation of caspofungin utilizing said intermediates.
1. Compounds of formula VII
or an acid addition salt thereof, wherein R 1 is —(CO)NH 2 , —CH 2 NH 2 or —CN;
R 2 =R 3 =H or R 2 and R 3 together form a cyclic boronate or borate ester;
X is a helping group selected from the group consisting of i) a five or six membered heterocyclic aromatic ring comprising at least one N-atom being a part of an imine-group, wherein said N-atom forms the point of connection to the cyclohexapeptide ring, and ii) tetrazolyl for which a nitrogen atom forms the point of connection to the cyclohexapeptide ring.
2. Compound according to claim 1 , wherein R 1 is —CH 2 NH 2 .
3. Compound of the formula V or V′
or an acid addition salt thereof, wherein R 1 is —(CO)NH 2 , —CH 2 NH 2 or —CN.
4. Compound according to claim 3 wherein R 1 is —CH 2 NH 2 .
5. Compound of the formula (VI)
or an acid addition salt thereof, wherein R 1 is —(CO)NH 2 , —CH 2 NH 2 or —CN.
6. Compound according to claim 5 wherein R 1 is —CH 2 NH 2 or an acid addition salt thereof.
7. The process of producing a compound of formula VIII
or a pharmaceutically acceptable salt thereof comprising the steps of
a) reacting a compound of formula VII or an acid addition salt thereof
wherein R 1 is —(CO)NH 2 , —CH 2 NH 2 or —CN;
R 2 =R 3 =H or R 2 and R 3 together form a cyclic boronate or borate ester;
X is a helping group selected from the group consisting of i) a five or six membered heterocyclic aromatic ring comprising at least one N-atom being a part of an imine-group, wherein said N-atom forms the point of connection to the cyclohexapeptide ring, and ii) tetrazolyl for which a nitrogen atom forms the point of connection to the cyclohexapeptide ring, with 1,2-diaminoethane to obtain a compound of formula VIII or a pharmaceutically acceptable salt thereof
and
b) optionally isolating the compound of formula VIII or a pharmaceutically acceptable salt thereof as obtained in step a).
8. The process of producing caspofungin (I)
or a pharmaceutically acceptable salt thereof comprising the steps of
a) reacting the compound of formula IX or an acid addition salt thereof
wherein R 1 is —(CO)NH 2 , —CH 2 NH 2 or —CN with i) a five or six membered heterocyclic aromatic compound comprising at least one N-atom being a part of an imine-group, or ii) tetrazole
to form a compound of formula VII
wherein R 1 and X are as defined above;
R 2 =R 3 =H or R 2 and R 3 together form a cyclic boronate or borate ester;
b) followed by substituting X with 1,2-diaminoethane to give a compound of formula VIII or a pharmaceutically acceptable salt thereof
c) optionally isolating the compound of formula I or a pharmaceutically acceptable salt thereof, provided that if R 1 in formula IX is —(CO)NH 2 or —CN a reduction is performed before or after step a) or b), respectively to afford the compound of formula I as the final product.
9. A process according to claim 8 wherein step a) to c), including the reduction of R 1 , are performed as a one-pot telescoped process.
10. A process according to claim 8 wherein X is introduced in reaction with pyridine and the compound of formula VII is
or an acid addition salt thereof.
11. A process according to claim 8 wherein X is introduced in reaction with tetrazole and the compound of formula VII is
or an acid addition salt thereof.