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Process for isolation of crystalline tacrolimus

A technology of tacrolimus and crystallization, applied in the field of separation and crystallization of tacrolimus, to achieve the effect of high yield

Inactive Publication Date: 2007-09-05
IVAX PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of an aqueous mobile phase remains a disadvantage of the method

Method used

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  • Process for isolation of crystalline tacrolimus
  • Process for isolation of crystalline tacrolimus
  • Process for isolation of crystalline tacrolimus

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Isolation of tacrolimus from whole fermentation broth

[0033] 10.0 liters of the total fermentation broth obtained by submerged culture of tacrolimus-producing Streptomyces sp. was diluted with 10.0 liters of 2-propanol and the suspension was stirred for 4 hours. The solid phase was separated by filtration and the filtrate was extracted twice with 1000 ml toluene. The combined toluene extracts were evaporated under reduced pressure to a volume of approximately 25 ml and according to HPLC analysis, the concentrate contained 2.12 g tacrolimus, 0.25 g ascomycin and 0.11 g tsucubamycin B. The concentrate was loaded onto a 20 g silver nitrate modified chromatography column packed with 200 g silica gel (Lichroprep Merck 60, 25-40 μm). The column was first washed with toluene (approximately 400 ml) and then with toluene progressively polarized with isobutyl methyl ketone (up to 60% (v / v)). The pure tacrolimus-containing fractions (HPLC monitoring) were combine...

Embodiment 2

[0035] Isolation of tacrolimus from dried mycelium

[0036] 40.0 kg of dry mycelium containing 0.21% tacrolimus according to HPLC analysis was prepared by processing 200 liters of fermentation broth obtained from submerged culture of tacrolimus-producing Streptomyces sp. The mycelium was extracted with 50% (v / v) acetone to obtain 40.0 liters of an aqueous extract, which was then extracted twice with 4 liters of toluene to obtain 15 liters of an organic extract. The organic extract was concentrated to a volume of about 1 liter. The concentrate was packed into a column containing 4.0 kg of silica gel (Merck 100, 63-200 μm). The column was washed first with toluene (approximately 30 liters), then with propanol progressively polarized toluene (up to 20% (v / v) acetone). Fractions containing tacrolimus (monitored by TLC) were combined and evaporated to dryness to give a residue (residue after first chromatography, 130 g) containing 61.6% tacrolimus, 7.9% Ascomycin and...

Embodiment 3

[0038] Preparation of silver nitrate modified silica gel

[0039] 10.0 g of crystalline silver nitrate were dissolved in 1000 ml of methanol under heating and 100 g of silica gel (Lichroprep Merck 60, 25-40 μm) were added to the solution, then the suspension was evaporated to dryness and the residue was dried at 60 mbar vacuum and 70 °C .

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Abstract

The invention is a simple process for separation of tacrolimus and its analogues, ascomycin and tsucubamycin B and preparation of enough pure crystalline tacrolimus. The process takes advantage of surprising properties of tacrolimus and involves extraction, purification and crystallization to produce purified crystalline tacrolimus.

Description

field of invention [0001] The invention relates to a method for separating crystalline tacrolimus from fermentation broth. Background of the invention [0002] Tacrolimus, also known as FK 506, is a naturally occurring macrolide with selective inhibitory effects on T-lymphocytes. It is used as an immunosuppressive drug. For example, tacrolimus was first described in patent US4,894,366 and EP 184,162, and then some scientific works also described it: H.Tanaka et al.J.Am.Chem.Soc.1987,109,5031-5033 and T. Kino et al. J. Antibiot. 1987, 40, 1249-1255. [0003] The preferred method for the preparation of tacrolimus is fermentation, although its total synthesis is also described eg in EP 378,318. It is difficult to isolate tacrolimus from the fermentation broth. Unfortunately, most tacrolimus-producing strains also produce ascomycin and some other macrolide compounds, such as tsucubamycin B, so, in pure tacrolimus The isolation method of crolimus must inv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/18C07D498/18
CPCC12P17/188C07D498/18
Inventor L·茨瓦克A·耶戈洛夫M·布奇塔P·布拉特尼J·萨特克
Owner IVAX PHARMA
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