Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-12-15
2003-09-09
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500
Reexamination Certificate
active
06617436
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for preparing a protected silylated clarithromycin oxime, such as 6-O-methyl-2′, 4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime (hereinafter “S-MOP oxime”), which include reacting a silyl oxime derivative with methylating agent while stirring in the presence of at least one solvent, where the solvent includes at least methyl tert-butyl ether (MTBE), and a base.
The present invention also relates to a method of converting the protected silylated clarithromycin oxime to clarithromycin, which includes reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1. The reaction mixture is cooled to about 20° C. and a base, preferably sodium hydroxide, is added. The method does not include any additional water addition to process clarithromycin.
The present invention further relates to a method of converting a protected silylated clarithromycin oxime, such as S-MOP oxime, to clarithromycin, which includes heating a mixture of the protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent. The invention further relates to the essentially oxime-free clarithromycin produced by such a method and pharmaceutical compositions containing the same.
BACKGROUND OF THE INVENTION
6-O-methyl erythromycin A (clarithromycin) is a semisynthetic macrolide antibiotic related to erythromycin A. It exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, Mycoplasma, and Chlamydia. It is stable under acidic conditions and is efficacious when administered orally. Clarithromycin is a useful therapy for infections of the upper respiratory tract in children and adults. Clarithromycin is stable under acidic conditions and is efficacious when administered orally.
The chemical structure of clarithromycin is:
Various methods of preparing 6-O-methylerythromycin A from erythromycin A have been described in the patent literature. One of the most effective methods includes the following steps: 1) protecting the 9-oxo group with a substituted oxime group, 2) protecting the hydroxyl groups in positions 2′ and 4″, 3) methylating the hydroxyl in position 6 to give a protected sililated clarithromycin oxime, and 4) removing the protecting groups at the 2′, 4″ and 9 position.
The third step, which comprises methylating the hydroxyl group at position 6, is performed in the presence of a solvent. This 6-O-methylation of various erythromycin derivatives in converting erythromycin A to clarithromycin has been reported in several U.S. Patents including U.S. Pat. Nos. 4,680,386 and 4,672,109.
U.S. Pat. No. 4,680,386 for example, describes a method of methylating the hydroxyl group at the 6 position by reacting the compound with a methylating agent in the presence of a base in an aprotic solvent at a temperature of between 0° C. and room temperature. The '386 patent describes the use of solvents including N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and a mixture of one or more of these solvents. U.S. Pat. No. 4,672,109 describes the use of solvents such as dimethyl sulfoxide, N,N-dimethylformamide, hexamethyl phosphoric triamide, a mixture of two or more of these solvents or a mixture of one of these solvents and tetrahydrofuran, 1,2-dimethoxyethane and the like. The '109 patent further describes a preferred embodiment of this step using a mixture of dimethyl sulfoxide and tetrahydrofuran. WO 97/19096 describes a mixture of solvents including N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethyl phosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile and ethyl acetate for use in the methylating step.
However, several of the above-described solvents are expensive, do not enable selective methylation, produce significant unwanted side products and/or cause complications during later phase separation steps.
The fourth step includes removing the protecting groups, and thus, converts protected silylated clarithromycin oxime to clarithromycin. Described methods of converting a protected silylated clarithromycin oxime, such as S-MOP oxime, to clarithromycin include reacting the protected silylated clarithromycin oxime with ethanol in the presence of an acid and a deoximating agent. The product of the reaction is then washed with water one or more times. The ethanol generally also contains water.
U.S. Pat. No. 4,990,602 has an ethanol to water ratio of 1:4 and does not involve cooling. U.S. Pat. No. 4,670,549 adds sodium hydroxide after cooling at an ethanol to water ratio of 1:3. Neither of these methods lowers the impurity content of clarithromycin.
SUMMARY OF THE INVENTION
The present invention relates to methods for preparing a protected silylated clarithromycin oxime, such as 6-O-methyl-2′, 4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime (“S-MOP oxime”), which include reacting a silyl oxime derivative with methylating agent while stirring in the presence of at least one solvent and a base, where the solvent includes methyl tert-butyl ether (MTBE). In the method for preparing the protected silylated clarithromycin oxime, the methylating agent is preferably one or more of methyl iodide, methyl bromide, dimethylsulfate, methyl p-toluenesulfonate, or methanesulfonate. The base is preferably sodium hydride, potassium hydroxide, or sodium hydroxide.
Further embodiments of the present invention relates to methods of converting a protected silylated clarithromycin oxime, such as S-MOP oxime, to clarithromycin. One such method includes reacting the protected silylated clarithromycin oxime with acid and a deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1. The reaction mixture is cooled to about 20° C. and a base, preferably sodium hydroxide solution, is added. In this method, no additional water is added to process clarithromycin. Another method of converting a protected silylated clarithromycin oxime to clarithromycin includes heating a mixture of the protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of deoximating agent. In the latter method, essentially oxime-free clarithromycin is produced, which contains less than 40 ppm of the corresponding oxime intermediate.
DETAILED DESCRIPTION OF THE INVENTION
Clarithromycin is described, inter alia, in the following publications, which are hereby incorporated herein by reference: U.S. Pat. Nos. 3,922,379, 4,331,803, 4,670,549, 4,672,109, 4,680,386, 4,808,411, 4,957,905, 4,990,602, 5,837,829, 5,844,105, 5,852,180, 5,858,986, 5,919,489, 5,932,710, and 5,945,405.
The terms “6-O-methylerythromycin A” and “clarithromycin” are used interchangeably herein and are meant to include clarithromycin in any form (such as crystalline Form 0, Form I, Form II or Form IV) or pharmaceutical salts thereof or mixtures thereof, as well as amorphous solids, syrups, or semisolids comprising clarithromycin in any state of purity, unless specified otherwise.
The present invention relates to increasing the product yield and unwanted side effects produced various steps included in converting erythromycin A to clarithromycin. Clarithromycin is prepared from erythromycin A by a variety of synthetic routes. Some of these routes include oximation steps and the use of a protected silylated clarithromycin oxime, such as an S-MOP oxime intermediate.
The synthetic routes of converting erythromycin A to clarithromycin that are improved herein, are those that utilize a protected silylated clarithromycin oxime intermediate, such an S-MOP oxime intermediate.
Synthetic routes of converting erythromycin A to clarithromycin include methylation of the 6-hydroxy group of e
Avrutov Iiya
Lewiner Elizabeth
Lifshitz Igor
Kenyon & Kenyon
Peselev Elli
Teva Pharmaceutical Industries Ltd.
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