Crystallization and purification of macrolides
First Claim
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1. A method of crystallizing a macrolide from a macrolide starting material comprising the steps of:
- a) combining, in a crystallization vessel, a macrolide starting material, a polar solvent, a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is a water-rich phase, and wherein the pH of the water-rich phase is at least about 7,b) maintaining the combination at for at least 1 hour, whereby a macrolide-rich phase is formed from which the macrolide crystallizes.
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Abstract
Provided is a method for crystallization and purification of a macrolide such as tacrolimus, sirolimus, pimecrolimus, or everolimus that includes the step of providing a combination of a macrolide, and a polar solvent, dopolar aprotic solvent, or hydrocarbon solvent at pH of 7 or above.
41 Citations
36 Claims
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1. A method of crystallizing a macrolide from a macrolide starting material comprising the steps of:
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a) combining, in a crystallization vessel, a macrolide starting material, a polar solvent, a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is a water-rich phase, and wherein the pH of the water-rich phase is at least about 7, b) maintaining the combination at for at least 1 hour, whereby a macrolide-rich phase is formed from which the macrolide crystallizes. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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15. A method of crystallizing a macro lide from a macrolide starting material comprising the steps of:
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a) combining a concentrate residue from whole-broth extraction of macrolide-containing biomatter in a polar solvent with a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is a water-rich phase, and wherein the pH of the water-rich phase is at least about 7, b) maintaining the combination at for at least 1 hour, whereby a macrolide-rich phase is formed from which the macrolide crystallizes. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
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29. A method of crystallizing a macrolide from a macrolide starting material comprising the steps of:
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a) combining, at a temperature of about 20°
to about 25°
C., macrolide starting material, ethyl acetate, n-hexane, and a water solution of a base selected from NaOH, KOH, Ca(OH)2, NH3, (C2H5)3N, diethylamine and pyridine whereby at least two phases are formed, one of which is a water-rich phase, wherein the pH of the water-rich phase is >
about 7,b) maintaining the combination at a temperature of about 20°
C. to about 25°
C. for at least 1 hour, whereby a macrolide-rich phase is formed from which macrolide crystallizes,c) maintaining the combination at a temperature of about 0°
C. to about 20°
C. for at least 1 hour, andd) recovering the macrolide that crystallizes. - View Dependent Claims (30, 31)
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32. A method of crystallizing a macrolide from a macrolide starting material comprising the steps of:
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a) combining, at a temperature of about 20°
to about 25°
C., a concentrate residue from whole-broth extraction of macrolide-containing biomatter in ethyl acetate, n-hexane, and a water solution of a base selected from NaOH, KOH, Ca(OH)2, NH3, (C2H5)3N, diethylamine and pyridine whereby at least two phases are formed, one of which is a water-rich phase, wherein the pH of the water-rich phase is >
about 7,b) maintaining the combination at a temperature of about 20°
C. to about 25°
C. for at least 1 hour, whereby a macrolide-rich phase is formed from which macrolide crystallizes,c) maintaining the combination at a temperature of about 0°
C. to about 20°
C. for at least 1 hour, andd) recovering the macrolide that crystallizes. - View Dependent Claims (33, 34)
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35. In a method for crystallizing a macrolide from a macrolide starting material, the step of combining the macrolide starting material, a polar solvent, a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is water rich, wherein the pH of the water-rich phase is at least about 7.
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36. In a method for crystallizing a macrolide from a concentrate residue from whole-broth extraction of macrolide-containing biomatter in a polar solvent, the step of combining the macrolide concentrate in the polar solvent, a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is water rich, wherein the pH of the water-rich phase is at least about 7.
Specification