# US 7,608,420 B2 · Process for the recovery of staurosporine from a fermentation broth

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- Number: US 7,608,420 B2
- Document ID: US7608420B2
- Status: Granted
- Kind: B2
- Application number: 10/553,911
- Filed: 2004-04-19
- Published: 2006-08-31
- Granted: 2009-10-27
- Earliest claimed: 2003-04-22
- Assignees: Lonza Ltd.
- Inventors: Kurt Eyer; Georges Kalbermatten; Jean-Peal Roduit; Alain Wellig
- Web page: https://patentgrep.com/patent/US7608420B2

## CPC

- C07D 498/22: in which the condensed system contains four or more hetero rings
- C12P 17/188: {Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms (ergot-alcaloids C12P17/183)}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}

## Abstract

Staurosporine of the formula (I) is recovered from a fermentation broth in a process comprising an ultrafiltration and a diafiltration step.

## Claims

### Claim 1

A process for the recovery of staurosporine of formula:
from a fermentation broth comprising the steps of:
i) adding tetrahydrofuran to the fermentation broth;
ii) ultrafiltering the dilute fermentation broth obtained in step i);
iii) optionally diafiltrating the retenate obtained in step ii) with a mixture of a water and tetrahydrofuran, and optionally combining the permeates of the ultrafiltration and the diafiltration;
iv) optionally adjusting the pH of the permeate obtained in step ii) or step iii) to at least 8.5;
v) concentrating the permeate;
vi) adjusting the pH of the concentrate obtained in step v) to at least pH 8.5, unless the pH of said concentrate is already at least 8.5; and
vii) collecting the precipitated staurosporine obtained in step vi).

### Claim 2 (depends on 1)

The process of claim 1, wherein the ratio of fermentation broth/tetrahydrofuran is between 5:1 and 0.5:1 (w/w).

### Claim 3 (depends on 2)

The process of claim 2 wherein the ratio of water/tetrahydrofuran of the mixture of water and tetrahydrofuran is between 5:1 and 0.5:1 (w/w).

### Claim 4 (depends on 3)

The process of claim 3 wherein the pH of the permeates obtained in steps ii) and iii) is adjusted to at least 8.5.

### Claim 5 (depends on 4)

The process of claim 4 wherein the pH of the concentrate is adjusted to at least 10.0.

### Claim 6 (depends on 5)

The process of claim 5 wherein precipitated staurosporine (I) is collected by centrifugation.

### Claim 7 (depends on 6)

The process of claim 6 wherein staurosporine (I) obtained in step vii) is recrystallized from a tetrahydrofuran/methanol mixture.

### Claim 8 (depends on 1)

The process of claim 1 wherein the ratio of water/tetrahydrofuran the mixture of water and tetrahydrofuran is between 5:1 and 0.5:1 (w/w).

### Claim 9 (depends on 1)

The process of claim 1 wherein the pH of the permeates obtained in steps ii) and iii) is adjusted to at least 8.5.

### Claim 10 (depends on 1)

The process of claim 1 wherein the pH of the concentrate is adjusted to at least 10.0.

### Claim 11 (depends on 1)

The process of claim 1 wherein precipitated staurosporine (I) is collected by centrifugation.

### Claim 12 (depends on 1)

The process of claim 1 wherein staurosporine (I) obtained in step vii) is recrystallized from a tetrahydrofuran/methanol mixture.

### Claim 13

A process for the recovery of staurosporine of formula:
from a fermentation broth comprising the steps of:
i) adding tetrahydrofuran to the fermentation broth;
ii) ultrafiltering the dilute fermentation broth obtained in step i);
iii) concentrating the permeate obtained in step ii);
iv) adjusting the pH of the concentrate obtained in step iii) to at least pH 8.5, unless the pH of said concentrate is already at least 8.5; and
v) collecting the precipitated staurosporine obtained in step iv).

### Claim 14

A process for the recovery of staurosporine of formula:
from a fermentation broth comprising the steps of:
i) adding tetrahydrofuran to the fermentation broth;
ii) ultrafiltering the dilute fermentation broth obtained in step i);
iii) adjusting the pH of the permeate obtained in step ii) to at least 8.5;
iv) concentrating the permeate from step iii);
v) adjusting the pH of the concentrate obtained in step iv) to at least pH 8.5, unless the pH of said concentrate is already at least 8.5; and
vi) collecting the precipitated staurosporine obtained in step v).

### Claim 15

A process for the recovery of staurosporine of formula:
from a fermentation broth comprising the steps of:
i) adding tetrahydrofuran to the fermentation broth;
ii) ultrafiltering the dilute fermentation broth obtained in step i);
iii) diafiltrating the retenate obtained in step ii) with a mixture of a water and tetrahydrofuran;
iv) adjusting the pH of the permeate obtained in step iii) to at least 8.5;
v) concentrating the permeate from step iv);
vi) adjusting the pH of the concentrate obtained in step v) to at least pH 8.5, unless the pH of said concentrate is already at least 8.5; and
vii) collecting the precipitated staurosporine obtained in step vi).

### Claim 16

A process for the recovery of staurosporine of formula:
from a fermentation broth comprising the steps of:
i) adding tetrahydrofuran to the fermentation broth;
ii) ultrafiltering the dilute fermentation broth obtained in step i);
iii) diafiltrating the retenate obtained in step ii) with a mixture of a water and tetrahydrofuran;
iv) combining the permeates of the ultrafiltration and the diafiltration;
v) adjusting the pH of the permeate obtained in step iv) to at least 8.5;
vi) concentrating the permeate from step v);
vii) adjusting the pH of the concentrate obtained in step vi) to at least pH 8.5, unless the pH of said concentrate is already at least 8.5; and
viii) collecting the precipitated staurosporine obtained in step vii).