US-20260125341-A1 - METHODS FOR SYNTHESIZING AND PURIFYING AMINOALKYL TETRACYCLINE COMPOUNDS

Abstract

Methods for the synthesis and purification of 9-amino alkyl tetracycline compounds are described.

Inventors

• Sean M. Johnston
• Tadeusz Warchol

Assignees

• PARATEK PHARMACEUTICALS, INC.

Dates

Publication Date

20260507

Application Date

20250523

Claims (2)

1. 1 . A method of synthesizing an aminoalkyl tetracycline compound, comprising: contacting a tetracycline compound with a N-hydroxymethyl phthalimide in the presence of a water scavenger and an acid under appropriate conditions, such that an aminomethyl tetracycline intermediate compound is formed.
2. 2 - 56 . (canceled)

Description

RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 60/926,461; filed on Apr. 27, 2007, the entire contents of which are hereby incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION The development of the tetracycline antibiotics was the direct result of a systematic screening of soil specimens collected from many parts of the world for evidence of microorganisms capable of producing bactericidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. The elucidation of the chemical structure of these compounds confirmed their similarity and furnished the analytical basis for the production of a third member of this group in 1952, tetracycline. A new family of tetracycline compounds, without the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967; and minocycline was in use by 1972. Recently, research efforts have focused on developing new tetracycline antibiotic compositions effective under varying therapeutic conditions and routes of administration. New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced tetracycline compounds. Examples include U.S. Pat. Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions. Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Hence, tetracyclines became known as “broad spectrum” antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., pneumococci and Salmonella). The rise of tetracycline-resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice. SUMMARY OF THE INVENTION In one embodiment, the invention pertains, at least in part, to a method of synthesizing an aminoalkyl tetracycline compound. The method includes contacting a tetracycline compound with an N-hydroxymethyl-phthalimide in the presence of a water scavenger and an acid under appropriate conditions, such that an aminomethyl tetracycline intermediate compound is formed. In another embodiment, the invention pertains, at least in part, to a method for the synthesis of an aminoalkyl tetracycline compound. The method includes: contacting a tetracycline compound with a N-hydroxymethyl-phthalimide in the presence of a water scavenger and an acid under appropriate conditions to form an aminomethyl tetracycline intermediate compound; treating the aminomethyl tetracycline intermediate compound with methylamine under second appropriate conditions to form a second aminomethyl tetracycline intermediate; and treating the second aminomethyl tetracycline intermediate under appropriate hydrogenation conditions, such that an aminomethyl tetracycline compound is formed. In another embodiment, the invention pertains, at least in part, to a method of purifying alkylaminomethyl minocycline compounds by injecting an aqueous low pH solution of the compound into an HPLC in a polar organic solvent gradient, and combining the product fractions containing the alkylaminomethyl minocycline compound. In yet another embodiment, the invention pertains, at least in part, to a method of removing hydrophobic impurities and oxidative degradents from an alkylaminomethyl minocycline compound. The invention includes dissolving the minocycline compound in an aqueous solution of a pH of 4.0-4.5, washing the aqueous solution with a non-polar organic solvent, and retaining the aqueous solution, such that hydrophobic impurities and oxidative degradents are removed from the alkylaminomethyl minocycline compound. In yet another embodiment, the invention also pertains, at least in part, to a method of removing the β epimer and by products from an alkylaminomethyl minocycline compound. The method includes dissolving the minocycline compounds in an aqueous solution of a pH of 7.5-8.5, washing the aqueous solution with a non-polar organic solvent, and retaining the org