Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-12-21
2002-09-24
Jones, Dwayne C. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S007200, C536S007400
Reexamination Certificate
active
06455680
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to an efficient deoximation technique for use in the synthesis of erythromycin derivatives, involving aryl thioimine intermediates. The aryl thioimine intermediates can be utilized in a method for protecting a ketone of a ketone-containing erythromycin derivative as a thioimine; a method for deoximating an oxime-containing erythromycin derivative, or a method for preparing a 6-O-alkyl erythromycin derivative. Presently preferred erythromycin derivatives have a C-9 oxime or a C-9 ketone.
BACKGROUND OF THE INVENTION
Erythromycins A through D, represented by Formula I and Table 1 shown below, are well-known and potent anti-bacterial agents, used widely to treat and prevent bacterial infection.
TABLE 1
Erythromycin
R
1
R
2
A
—OH
—Me
B
—H
—Me
C
—OH
—H
D
—H
—H
As with other anti-bacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify and synthesize new erythromycin derivative compounds which possess improved anti-bacterial activity, which have lower potential for developed resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms.
Generally, 6-O-alkyl derivatives of erythromycin are known as anti-bacterial agents. 6-O-methyl erythromycin A (clarithromycin A, disclosed in U.S. Pat. No. 4,331,803) and 6-O-methyl erythromycin B (clarithromycin B, disclosed in U.S. Pat. No. 4,496,717) are potent macrolide antibiotics.
More recently, 6-O-substituted derivatives of erythromycin having improved antibacterial activity have been disclosed in U.S. Pat. Nos. 5,866,549; 5,872,229; 5,919,916; 5,932,710; 6,040,440; 6,075,011 and 6,124,269 among others.
Synthetic techniques for 6-O-substituted erythromycin derivatives generally involve protection of a C-9 ketone as an oxime, followed by protection of the 2′- and 4″-hydroxyl groups prior to 6-O-alkylation. Subsequent to 6-O-alkylation, the protecting groups are removed.
The deoximation reaction has been carried out according to methods described by Greene and Wuts in
Protective Groups in Organic Synthesis,
2nd Ed., John Wiley & Son, Inc, 1991, and others. Examples of the deoximating agent are inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate and potassium metabisulfite among others. Deoximation may also be accomplished by treatment with an inorganic nitrite salt, for example, sodium nitrite or potassium nitrite, in the presence of acid. Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more of the above solvents. The deoximation reaction has been carried out in the presence of an organic acid such as formic acid, acetic acid or trifluoroacetic acid, but may be accomplished with hydrochloric acid also.
However, the conventional techniques described above have certain disadvantages. For example, in a typical deoximation with an erythromycin oxime with sodium bisulfite, approximately 30-40% of the product may be lost as a result of decomposition, due to the relatively harsh reaction conditions. Therefore, milder methods for more efficient deoximation would be advantageous; and such a method for a more efficient deoximation could be advantageously utilized in a method for ketone protection in ketone-containing erythromycin derivatives, or in a method for making 6-O-alkyl substituted erythromycin derivatives.
BRIEF SUMMARY OF THE INVENTION
The invention is directed to a method for protecting a ketone of a ketone-containing erythromycin derivative as a thioimine comprising the steps of:
reacting a ketone of a ketone-containing erythromycin derivative with a hydroxamating agent to form an oxime; and then,
reacting said oxime with a trialkyl phosphine and an aryl disulfide to form an aryl thioimine.
In the method, the ketone may be a C-9 ketone, and the aryl thioimine may be a C-9 aryl thioimine. The method may also include deprotecting the aryl thioimine in aqueous acidic solution to form a ketone-containing erythromycin derivative. The C-9 ketone containing-erythromycin derivative may have a hydroxyl group at C-6. Furthermore, the C-9 ketone is protected to alkylate C-6 with an alkylating agent. A presently preferred ketone-containing erythromycin derivative is erythromycin A and a presently preferred aryl thioimine is 9-phenylthioimino erythromycin. Moreover, the arylthioimine can be hydrolyzed to an imine with a hydrolyzing agent.
The invention is also directed to a method for deoximating a 6-O-substituted oxime-containing erythromycin derivative comprising the steps of:
reacting an oxime of a 6-O-substituted oxime-containing erythromycin derivative with a trialkyl phosphine and an aryl disulfide to form an aryl thioimine; and then,
hydrolyzing said aryl thioimine in aqueous acidic solution to form a ketone-containing 6-O-substituted erythromycin derivative.
The 6-O-substituted oxime-containing erythromycin derivative may be a C-9 oxime-containing, 2′-hydroxyl-containing, 4″-hydroxyl-containing, C-6-hydroxyl-containing erythromycin derivative. For the practice of this method, the 2′-hydroxyl and 4″-hydroxyl of the C-9 oxime-containing, 2′-hydroxyl-containing, 4″-hydroxyl-containing, C-6-hydroxyl-containing erythromycin derivative can be protected with at least one hydroxyl-protecting agent to form a 2′- and 4″-hydroxyl protected aryl thioimine after aryl thioimine formation. Moreover, after such protection the 2′- and 4″-hydroxyl protected aryl thioimine can be alkylated with an alkylating agent to form a 2′- and 4″-hydroxyl protected, C-6-O-alkylated aryl thioimine. A presently preferred 2′- and 4″-hydroxyl protected, C-6-O-alkylated aryl thioimine is 9-phenylthioimino-6-O-propenylquinolinylerythromycin-2′,4″-dibenzoate, and a presently preferred ketone-containing 6-O-substituted erythromycin derivative is 6-O-propenylquinolinylerythromycin-2′,4″-dibenzoate.
The invention is also directed to a method of preparing a 6-O-alkyl derivative of a C-9 ketone-containing, C-6 hydroxyl-containing, 2′-hydroxyl-containing, 4″-hydroxyl-containing erythromycin derivative comprising the steps of:
reacting the C-9 ketone of a C-9 ketone-containing, C-6 hydroxyl-containing, 2′-hydroxyl-containing, 4″-hydroxyl-containing erythromycin derivative with a hydroxamating agent to form a C-9 oxime;
derivatizing said C-9 oxime with a trialkyl phosphine and an aryl disulfide to form a C-9 aryl thioimine;
protecting said 2′-hydroxyl and said 4″-hydroxyl of said C-9 aryl thioimine with at least one hydroxyl-protecting agent to form a 2′ and 4″-hydroxyl protected C-9 aryl thioimine;
alkylating said C-6-hydroxyl of said 2′ and 4″-hydroxyl protected C-9 aryl thioimine with an alkylating agent to form a C-6-O-alkylated 2′ and 4″-hydroxyl protected C-9 aryl thioimine;
deoximating said 2′ and 4″-hydroxyl protected C-6-O-alkylated C-9 aryl thioimine in aqueous acidic solution to form a 2′ and 4″-hydroxyl protected C-6-O-alkylated C-9 keto-erythromycin derivative; and then isolating the desired product.
For the practice of this method, the 2′ and 4″-hydroxyl protected C-6-O-alkylated C-9 keto-erythromycin derivative can be deprotected to form a 2′ and 4″-hydroxyl, C-6-O-alkylated C-9 keto-erythromycin derivative. A presently preferred 2′ and 4″-hydroxyl protected C-6-O-alkylated C-9 keto-erythromycin derivative is 6-O-propenylquinolinylerythromycin-2′,4″-dibenzoate.
For the practice of any of the methods of the present invention, the
Abbott Laboratories
Donner B. Gregory
Jones Dwayne C.
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