Granted Patent B2

US 9,522,872 · App. 12/217,709 · Granted Dec 20, 2016

Abstract

Claims (35)

1. A method for synthesizing a 9-substituted minocycline compound of the formula:

comprising:

a) reacting a 9-halogenated minocycline with carbon monoxide, a first palladium catalyst, a silane and a base to generate a 9-carboxaldehyde substituted minocycline compound of the formula:

and

b) reacting said 9-carboxaldehyde substituted minocycline compound with neopentyl amine under hydrogenolysis or reductive amination conditions to generate said 9-substituted minocycline compound of the formula:

or a pharmaceutically acceptable salt or ester thereof;

wherein said hydrogenolysis conditions comprise a second palladium catalyst, an ammonium compound and one or more solvents; and

wherein said reductive amination conditions comprise a reducing agent and a solvent.

2. The method of claim 1 , wherein said 9-halogenated minocycline is a 9-iodine substituted minocycline, a 9-chlorine substituted minocycline, or a 9-bromine substituted minocycline.

3. The method of claim 1 , wherein said first palladium catalyst is Pd(OAc) 2 , PdCl 2 (tBu 2 PhP) 2 [dichlorobis(di-tert-butylphenylphosphine palladium (II)] or PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].

4. The method of claim 1 , wherein said first palladium catalyst is Pd(OAc) 2 or PdCl 2 (tBu 2 PhP) 2 .

5. The method of claim 1 , wherein said silane is triethylsilane.

6. The method of claim 1 , wherein said base is sodium carbonate or diisopropylethylamine.

7. The method of claim 1 , wherein said reaction in step a) comprises a solvent.

8. The method of claim 7 , wherein said solvent is methylpyrrolidone or a mixture of tetrahydrofuran and dimethylformamide.

9. The method of claim 1 , wherein said reaction in step a) comprises xantphos or InCl 3 .

10. The method of claim 1 , wherein said reductive amination conditions in step b) comprise methanol.

11. The method of claim 1 , wherein:

step a) comprises:

a1) mixing 9-iodominocycline, sodium carbonate and PdCl 2 (tBu 2 PhP) 2 in a mixture of tetrahydrofuran and dimethylformamide in the presence of carbon monoxide;

a2) heating the mixture from a1);

a3) adding triethylsilane to the mixture from a2); and

a4) reacting the mixture from a3) such that a 9-carboxaldehyde substituted minocycline is generated; and

step b) comprises:

b1) hydrogenating said 9-carboxaldehyde substituted minocycline in the presence of neopentyl amine, 5% Pd—C, wet and methanol.

12. The method of claim 11 , further comprising after a4) the following steps:

a5) filtering the reaction mixture from a4);

a6) adding the filtrate from a5) to tert-butyl-methyl-ether; and

a7) drying the precipitate from a6).

13. The method of claim 11 , further comprising after b1) the following steps:

b2) diluting the mixture from b1) with sodium carbonate and filtering the mixture;

b3) adjusting the pH of the filtrate from b2);

b4) extracting the filtrate from b3) with dichloromethane; and

b5) drying the extracts from b4).

14. The method of claim 2 , wherein said 9-halogenated minocycline is a 9-iodine substituted minocycline.

Assignments (12)