Methods for synthesizing substituted tetracycline compounds

Patent metadata

Field	Value
Publication number	US-9522872-B2
Application number	US-21770908-A
Country	US
Kind code	B2
Filing date	Jul 7, 2008
Priority date	Jul 6, 2007
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

Methods of synthesizing substituted tetracycline compounds are provided.

First claim

The invention claimed is:

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.

Assignees

• Seyedi Farzaneh
• Warchol Tadeusz
• Grier Mark
• Paratek Pharm Innc

Inventors

• Seyedi Farzaneh
• Warchol Tadeusz
• Grier Mark

Classifications

• C07C2603/44

  Naphthacenes; Hydrogenated naphthacenes · CPC title

• C07C231/12 Primary

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C237/26

  of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline · CPC title

• C07C2103/44

  Chemistry & Metallurgy · mapped topic