Field of the Invention

The present invention is provided an improved process for the isolation of Minocycline free base, wherein all impurities are controlled, especially impurity 4-epimer minocycline to very low levels.

Background of the Invention
Tetracyclines are a group of broad-spectrum antibiotics that contain four hydrocarbon rings. Tetracycline itself was first described in J. Am. Chem. Soc, 1953, 75, 4621. Various tetracycline derivatives have been described since, examples of which are described in U.S. 2,980,584; U.S. 2,990,331; U.S. 3,062,717; U.S. 3,165,531; U.S. 3,226,436; U.S. 3,454,697; U.S. 3,557,280; U.S. 3,674,859; U.S. 3,957,980; U.S. 4,018,889; U.S. 4,024,272; and U.S. 4,126,680.

Tetracycline derivatives are chemically stable in strong mineral acids, particularly in concentrated sulfuric acid, and, therefore, can be subjected to certain chemical transformations {J. Am. Chem. Soc., 1960, 8(2), 1253; J. Med. Chem., 1962, 5(3), 538). Extensive research has been performed on nitration and halogenation of tetracyclines that afforded 7- and/or 9-halo/nitro derivatives.

An effective method of isolating a product from the nitration reaction mixture is precipitation with diethyl ether (GB 876,500; EP 535346; US 5,248,797; US 5,281,628; US 5,401,863). Although ethers are suitable solvents for precipitation of organic salts, diethyl ether being the most widely used for this purpose, such solvents are inconvenient for industrial processes because of related safety issues.

An alternative isolation process is described in J. Med. Chem., 1962, 5(3), 538, and is performed by diluting the reaction mixture with water followed by extraction with 1-butanol. The desired solid product is then isolated from the organic solution by means of evaporation to dryness. This alternative process is limited to nitrated tetracycline derivatives that are soluble in 1-butanol and is applicable to a limited number of tetracycline derivatives.

Isolation of other tetracycline derivative such as minocycline using diethyl ether, according to the prior art (U.S. 3,901,942; J. Med. Chem., 10, 44, 1967) afforded a hardly filterable and very hygroscopic solid, even after washing it on a filter several times with ether. Although suspending the initially isolated product in another portion of ether afforded easily processable non-hygroscopic material, the total amount of ether used for finally isolating the product in a stable dry form was very large.

An alternative isolation process of minocycline is described in U.S. 4,918,208 and is performed by subjecting it to adsorption on non-ionic adsorption resin after treating it with hydroxyl amine sulfate or urea. The use of the adsorption resin on commercial scale is not viable.

Hence, there is a need in the art for a new/improved process for the isolation of highly pure minocycline free base, which is simple, cost effective, eco-friendly and commercially suitable process by over coming the problems encountered in the above prior art processes.

Objective of the invention
An object of the invention is to produce an economically and industrially viable process for isolating minocycline in highly pure form.

Summary of the Invention
In one of the embodiments of the present invention provides an improved process for the isolation of minocycline, based on extraction in organic solvent at suitable pH.

In a preferred embodiment, the process is advantageous to reduce the impurity level in final product as well as the cost of production on industrial scale.

Detailed description of the Invention
The present invention discloses in its aspect an improved process for the isolation of minocycline.

The object of the present invention is to provide a process, which minimizes the cost of production and impurity level in the final product.

One preferred embodiment of the invention relates to a process for the isolation of minocycline comprising, extracting the crude minocycline from the reaction mixture in organic solvent from aqueous layer after adjusting the pH in the range of 4-6 using base, followed by the evaporation of organic layer to get the pure minocycline.

Preferably, the solvents used herein is selected from the group consisting of but not limited to halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane and the base used herein is selected from the group consisting of but not limited to inorganic base.

The present invention has under mentioned advantages on the prior art:
1. Extraction technique helps in reducing the 4-epimer impurity and other impurities level up-to around 1% or less which are coming around 8-15% before extraction.
2. Extraction technique helps in removing the main reaction by-product i.e. p-dimethylaminobenzenesulfonic acid formed during the reaction. The by-product remains in aqueous layer thus provide the extracted organic layer free of the same.
3. Use of resin Diaion HP-20 reported in prior art is not economically and operationally feasible at industrial scale thus has been replaced with extraction method.
4. Extraction of minocycline base in organic layer also helps in increasing the yield up-to the level of above 95% than the reported yield in prior art i.e. 85%.