Process for the preparation of 9-deoxo-9a-homoerythromycin A, modified in the C-4″ of the cladinose ring by an epoxide group
View Patent ↗The present invention concerns a process for the preparation of the compound of formula The compound of formula (1) is the key intermediate in the synthesis of some antibacterial agents of the triamilide class, such as Tulathromycin, useful to treat bacterial and protozoa infections.
1. Process for the manufacture of a compound of formula
comprising the steps of:
(i) protecting the hydroxyl group in the C-2′ and, optionally, the C-9 oxime group of erythromycin A 9-(E)-oxime to obtain a compounds of formula
wherein R 1 is a hydroxyl protecting group and R 2 is hydrogen or an oxime protecting group;
(ii) oxidizing the compound of formula (3) in the presence of an oxidizing agent in order to obtain a compound of formula
wherein R 1 and R2 are as defined above;
(iii) converting the compound of formula (4) to the corresponding epoxide of formula
wherein R 1 and R2 are each as defined above;
(iv) removing the protecting group R 1 and optionally R 2 of the compound of formula (5) to yield the compound of formula
(v) subjecting the oxime of formula (6) to a Beckmann rearrangement in order to obtain the corresponding 6,9-iminoether of formula
and
(vi) reducing the iminoether of formula (7) to obtain the epoxide of formula (1).
2. The process according to claim 1 , wherein the oxidation of the compound of formula (3) in step (ii) is performed with dimethylsulfoxide which is activated by trifluoroacetic anhydride, oxalyl chloride, a polyphosphoric acid, a pyridine-SO 3 complex or acetic anhydride.
3. The process of claim 1 , wherein R 1 and R 2 in formulae (3) and (4) are both C 2 -C 4 -alkanoyl.
4. The process of claim 1 , wherein the preparation of the epoxide of formula (5) according to step (iii) comprises reacting the carbonyl group in the C-4″ position with a sulfonium methylide ion.
5. The process of clairnl, wherein the removal of the protecting group of R 1 and optionally R 2 is carried out by a treatment with a C i -C 4 -alkanol.
6. The process of claim 1 , wherein the preparation of the compound of formula (7) according to step (v) is performed by reacting the oxime of formula (6) with a sulfonic acid derivative.
7. The process of claim 1 , wherein the reduction of the iminoether of formula (7) according to step (vi) is carried out with a complex metal hydride as reducing agent.
8. A process for the manufacture of Tulathromycin, which comprises:
(i) protecting the hydroxyl group in the C-2′ and, optionally, the C-9 oxime group of erythromycin A 9-(E)-oxime to obtain a compound of formula
wherein R 1 is a hydroxyl protecting group and R is hydrogen or an oxime protecting group;
(ii) oxidizing the compound of formula (3) in the presence of an oxidizing agent in order to obtain a compound of formula
wherein R 1 and R are as defined above;
(iii) converting the compound of formula (4) to the corresponding epoxide of formula
wherein R 1 and R are each as defined above;
(iv) removing the protecting group R 1 and optionally R 2 of the compound of formula (5) to yield the compound of formula
(v) reacting the compound of formula (1) with n-propylamine.
9. The process of claim 2 wherein the dimethylsulfoxide is activated by trifluoroacetic anhydride.
10. The process of claim 3 wherein the C 2 -C 4 -alkanoyl is acetyl.
11. The process of claim 5 wherein the C 1 -C 4 -alkanol is methanol.
12. The process of claim 6 wherein the sulfonic acid derivative is toluenesulfonyl chloride.