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PROCESS FOR THE PREPARATION OF CALCIUM–BIS-[9-[[(2E)-4-[2S,3R,4R,5S)-3,4-DIHYDROXY-5-[[(2S,3S)-3-[1S,2S)-2-HIDROXY-1-METHYLPROPYL]OXIRANYL]-METHYL]-TETRAHYDRO-2H-PYRAN-2-yl]-3-METHYLBUT-2-ENOYL]-OXY]-NONANOATE]-DIHYDRATE

IP.com Disclosure Number: IPCOM000170588D
Publication Date: 2008-May-21
Document File: 3 page(s) / 23K

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   PROCESS FOR THE PREPARATION OF CALCIUM-BIS-[9-[[(2E)-4- [2S,3R,4R,5S)-3,4-DIHYDROXY-5-[[(2S,3S)-3-[1S,2S)-2-HIDROXY-1- METHYLPROPYL]OXIRANYL]-METHYL]-TETRAHYDRO-2H-PYRAN-2- yl]-3-METHYLBUT-2-ENOYL]-OXY]-NONANOATE]-DIHYDRATE Calcium-bis-[9-[[(2E)-4-[2S,3R,4R,5S)-3,4-dihydroxy-5-[[(2S,3S)-3-[1S,2S)-2- hydroxy-1-methylpropyl]oxiranyl]-methyl]-tetrahydro-2H-pyran-2-yl]-3-methylbut- 2-enoyl]-oxy]-nonanoate]-dihydrate (PSECA) a chemical having the following structure:

O
H O

OH

    is an antibiotic derived from pseudomonic acid. It is currently marketed in the United States as Bactroban®. Bactroban® is recommended for treatment of secondarily infected traumatic skin lesions caused by strains of Stephylococcus aureus and Streptoeoccuspyogenes.

    PSECA can be prepared by a process comprising provding a solution of PSECA in C1-C3 alcohols, and adding water to the solution to obtain a suspension comprising crystalline PSECA.

    The process comprises dissolving [9-[[(2E)-4-[2S,3R,4R,5S)-3,4-dihydroxy-5- [[(2S,3S)-3-[1S,2S)-2-hydroxy-1-methylpropyl]oxiranyl]-methyl]-tetrahydro-2H-pyran- 2-yl]-3-methylbut-2-enoyl]-oxy]-nonanoate] ("PSE") in a solvent selected from the group consisting of: C1-C3 alcohols, combining the said solution with potassium hydroxideto obtain a second solution, combining the second solution with calcium chloride to obtain a third solution comprising of PSECA, and adding water to obtain PSECA.

    The preferred C1-3 is methanol. Preferably, the dissolution of PSE in the C1-3 alcohol is done at a temperature of about 20°C to about 35°C,more preferably, at atemperature of about 20°C to about 30°C.

-

O O

H

Ca2+

H

H

H

H

O

OH

O

H

HO H

2

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    Preferably, the second solution obtained has a pH of about 10.3 to about 10.6. The second solution can be seeded with potassium chloride crystals, prior to the addition of calcium chloride. Then the addition of the calcium chloride methanolic solution provides a third solution comprising of PSECA and potassium chloride. Preferably, the third solution has a pH of about 8.5 to about 8.6.

    The third solution is then cooled providing a precipitate of potassium chloride. Preferably, the cooling is to a temperature of about 8°C to about 0°C. More preferably,...