Title of Invention

"PROCESS FOR THE PRODUCTION OF HIGH-PURITY RAC-1-[4-[2-HYDROXY-3-(5-QUINOLYLOXY) PROPYL]-PIPERAZIN-1-YL]-2,2-DIPHENYLETHAN-1-ONE FUMARATE AND HIGH-PURITY RAC-1-[4-[2-HYDROXY-3-(5-QUINOLYLOXY)PROPYL] PIPERAZIN-1-YL]-2,2-DIPHENYLETHAN-1-ONE FUMARATE"

Abstract A process for the production of high-purity racl-(4-[2-hydroxy-3-(5-quinolyloxy)propyl]- piperazin-1-yl)-2,2-diphenylethan-1-one fumarate, comprising reacting a) an epoxytosylate of structure I b) 5-hydroxyquinoline (II) and cesium carbonate in acetone and at a temperature of 35-60°C, to form the 5-(2,3-epoxypropoxy)-quinoline of formula III and then reacting said formula III with.
Full Text
The invention relates to a process for the production of high-purity rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate as well as rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-l-yl}-2,2-diphenylethan-l-one fumarate at a purity of at least 99.55%.
The multidrug-resistance modulator rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate, its production and use as carcinostatic pharmaceutical agent, in addition to other derivatives of this compound, is described in EP 575890.
According to the process for the production of pure rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate that is described in EP 575890, the free base 5-[3-{4-(2,2-diphenylacetyl)piperazin-l-yl}-2-hydroxypropoxy]quinoline is first isolated as a crude product by coupling the two components epoxiline (B) (5-(2,3-epoxypropoxy)-quinoline) and diphenepiperazide (C) (N-(2,2-diphenylacetyl)piperazine). This reaction contains two partial stages. First, the epoxylate is reacted with hydroxyquinoline (A). In the second step, the epoxiline (B) (5-(2,3-epoxypropoxy)-quinoline) is opened by diphenepiperazide (C) (N-(2,2-diphenylacetyl)piperazine); it produces the secondary alcohol (D). This reaction takes place in ethanol; water catalyzes the reaction. The working-up/isolation is then carried out by precipitation from acetone/water and drying in a vacuum at 60°C.
The total reaction is produced from the diagram below:

(Table Removed)

[Key:]
Hydroxyquinolin -; hydroxyquinoline
Epoxilin - epoxiline
Diphenpiperazid ~ diphenepiperazide
VE-Wasser = VE water
-quinolin — -quinoline
In the next step, a very expensive purification process follows the isolation of the free base, which still contains many contaminants (purity of the crude product typically about 80%). After the free base is treated with activated carbon and after the fumarate is formed in methanol, the free base is produced again for purification by treatment with dilute sodium hydroxide solution. Then, as a last step, repeated fumarate formation is carried out. The two fumarate formations are identical as far as processing is concerned and are distinguished only by the batch size (T. Suzuki et al., J. Med. Chem. (1997) 40, 2047) (JP 2000281653). Starting from the free base crude product, the typical laboratory yield for this purification sequence is 45% of theory.
In this case, not only the low yield (over 50% loss in the final stage) but also the expensive technical execution, which binds many operational capacities and thus produces elevated costs, is disadvantageous in this process. Especially disadvantageous in this case is the extremely poor filterability of the free base, which must be partially filter-dried over several weeks.

Despite the high expense as far as processing is concerned, the extremely high purification requirements of rac- l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-l-yl}-2,2-diphenylethan-l one fumarate are not always achieved in a completely satisfactory manner according to this known process.
Also, the process that is described in EP 575 890 does not provide any reasonable results in the scale-up.
The following diagram provides an overview of the individual reactions:
(Table Removed)
[Key:]
freie Base des = free base of -quinolins ~ quinoline Fumarsaure - fumaric acid Aktivkohle = activated carbon
Fumarat des - fumarate of

Wasser = water
freie gereinigte Base des = free purified base of
reincs Fumarat des - pure fumarate of
It has now been found that with the process according to the invention, these known drawbacks can be overcome. In the process according to the invention, the epoxiline (B) and diphenepiperazide (C) are first also coupled by opening the epoxide. Then, however, not the free base (D), but rather, after the solid fumaric acid is added directly, fumarate salt (E) is isolated as a crude product.
The subject of the application is thus a process for the production of high-purity rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl(--2,2-diphenylethan-l-one fumarate, which is characterized in that first
a) an epoxytosyiate of structure I

(Figure Removed)
can be reacted with
b) 5-hydroxyquinoline (II)
(Figure Removed)

and cesium carbonate in a suitable solvent and at a suitable temperature to form the 5-(2,3-epoxypropoxy)-quinoline of formula III



and then the 5-(2,3-epoxypropoxy)-quinoline of formula III
(Figure Removed)
is reacted with N-(2,2-diphenylacetyl)piperazine of formula IV

(Figure Removed)
in a suitable solvent and at a suitable temperature with the subsequent addition of solid fumaric acid to form crude rac-1 - {4-[ 2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1 -yl {-2,2-diphenylethan-l -one fumarate of formula V
(Figure Removed)
and then

d) the thus formed crude rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-1-one fumarate (V) is isolated and is dissolved in a solvent mixture that consists of methanol and methylene chloride, is treated with activated carbon, and then is filtered through a pressure filter with silica gel as a column material, and the thus obtained pure rac-l-)4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate (V) is crystallized from a suitable alcohol
The reaction is preferably carried out in a temperature range of 35 to 60°C.
Suitable solvents are, e.g., ketones, such as acetone, methyl-isobutylkelone, etc., alcohols, such as methanol, ethanol, isopropanol etc., amides, such as dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone, etc.
In comparison to the known process, the crude rac-l-{4-[2-hydroxy-3-(5-
quinolyloxy)propyl]-pipera7in-l-yl}-2,2-diphenylethan-l-one of process stage c) that is isolated via the process according to the invention already exhibits a dramatically increased purity of 90-96%.
The purification step that is included in process stage d) is preferably performed in a solvent mixture that consists of MeOH/MeCl2 at a ratio of 3:7, v:v.
Norit SX Plus is preferably used as activated carbon.
The amount of silica gel is preferably 3x the amount relative to the starting material.
The temperature in the crystallization in process stage (d) is preferably 0°C.
The typical laboratory yield for purification step (d) is 84% of theory.

Production Example
Production olrac-l-{4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-1-one t'umarate
A) Under nitrogen, 44.2 g of 5-hydroxy-quinoline and 151.9 g of cesium carbonate are
added together with 560 ml of acetone at room temperature and stirred for 30 minutes at a bath
temperature of 60°C.
At an internal temperature of 5()°C, 73.0 g of 5-(2,3-epoxypropoxy)-quinoline, dissolved in 153.3 g of dichloromethane, is added. Stirring is continued for two hours at 50°C. The batch is filtered at 50°C. The filter residue (inorganic salts) is rewashed with 560 ml of acetone heated to 50°C. Then, 85.4 g of N-(2,2-diphenyl-acetyl)piperazine is added, and it is concentrated by evaporation at a bath temperature of 40°C in a vacuum to 374 g of final weight. Then, 374 g of VE.-water is added, and it is stirred for 2 hours at 40°C. Then, 255 g of acetone and 201 g of VE-water are added. The batch is cooled to room temperature, and 89.1 g of fumaric acid in solid form is added. It is stirred for 60 minutes at a bath temperature of 60°C and then stirred for 2 hours at 0°C, Then, the solid is suctioned off and rewashed with 150 ml of ice-cold methanol. The filter residue is dried at 6()°C in a vacuum.
Yield: 65-85% of theory
B) 56.0 g of the thus produced rac-1 -{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-
yl} -2,2-diphenylethan-1 -one fumarate was mixed under nitrogen and at room temperature with
5.6 g of activated carbon, Norit SX plus, 672 ml of methanol and 1008 ml of dichloromethane.
The suspension that is produced is heated at a bath temperature of 75°C to reflux temperature and is
kept at reflux for 30 minutes. At an internal temperature of 40°C, rac-l-{4-[2-hydroxy-3-(5-
quinolyloxy)propyl]-pipcra/in-l-yl}-2,2-diphenylethan-l-one fumarate goes into solution. Then, the hatch is hot-filtered through 300% silica gel, and the silica gel is rewashed with 560 ml of a mixture that consists of 168 ml of methanol and 392 ml of dichloromethane at room temperature R 1. The solution is concentrated by evaporation at a bath temperature of 40°C and an initial vacuum of 400 mbar to a final volume of 517 ml. The final vacuum is 350 mbar. The distilled volume corresponds approximately to the volume difference (about 1.7 1). 404 ml of methanol is added, such that a final volume of 921 ml is reached. The solution is cooled to 0°C, whereby the product precipitates. The suspension that is produced is stirred for 2 hours at 0°C and then filtered through a paper filter. The filter residue is washed with 56.0 ml of ice-cold methanol. The filter residue is dried at 60°C and dried in a vacuum at 100 mbar for 10 hours.
Yield (uncorr.): 47.29 g ( 84.45% of the experiment)
Purity: 99.65% (HPLC, 100% method)

Comparison of the Purification Process that is Known in the Literature with the Purification Process According to the Invention

(Table Removed)
From the results, it can be seen that the total yield of rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate (V) can be increased by more than 50%.
From the results, it can also be seen that with the process according to the invention, the necessary extremely high purities can be reached, by which the technical expense could be greatly reduced at the same time. It can also be noted that contaminants (VU) 1-4, which are formed during the reaction, can be completely avoided.
A comparison of feedstocks, which had been produced according to the known process and according lo the process of the invention, is indicated in the table below.
(Table Removed)
n. d. = not detectable, since under the detection limit
*) Dependent on the purity of the commercially available products (educts): if contained in the
educt at Additional contaminants, which are formed during synthesis and also are removed effectively by the process according to the invention:
(Table Removed)

The subject ofthis invention is thus also rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylelhan-l-one furaarate at a purity of more than 98.54%.
In addition, a subject ofthis invention is also rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-pipera/in-l-yl}-2,2-diphenylethan-l-one fumarate at apurity of at least 98.55%, especially at a purity of at least 99.55%, especially at a purity of at least 99.65% as well as at a purity of at least 99.84%.
The process according to the invention is suitable in particular for the production of rac-1-!4-|2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate on a process-technology scale. Thus, with this process, rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate can be produced for the first time in amounts of more than 1000 g in the purity described.
A subject ofthis invention is also rac-l-{4-[2-hydroxy-3-(5-quinolyIoxy)-propyl]-piperazin-1 -yl }-2,2-diphenylethan-1 -one fumarate, which as a contaminant comprises less than 0.1 %, preferably less than 0.01%, of at least one of the individual contaminants (VU 1 - VU 11).
With conventional purification processes, such as chromatography, high-pressure liquid chromatography (HPLC), ion exchangers, etc., rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)-propyl]-piperazin-l-yl}-2,2-diphenylcthan-l-one fumarate cannot he produced in the purity according to the invention.



WE CLAIM:
1. A process for the production of high-purity rac-l-(4-[2-hydroxy-3-(5-quinolyloxy)propyl]- piperazin- l-yl)-2,2-diphenylethan-1-one fumarate, comprising reacting
a) an epoxytosylate of structure I
(Formula Removed)
with
b) 5-hydroxyquinoline (II)
(Formula Removed)
and cesium carbonate in acetone and at a temperature of 35-60°C, to form the 5-(2,3-epoxypropoxy)-quinoline of formula III
(Formula Removed)

and then reacting said formula III with c) N-(2,2-diphenylacetyl)piperazine of formula IV
(Formula Removed)

in a acetone and at a temperature of 35-60°C with the subsequent addition of solid fumaric acid to form crude rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] -piperazin-1-yl}-2,2 -diphenylethan-1-one fumarate of formula V
(Formula Removed)





and then d) the thus formed crude rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate (V) is isolated and is dissolved in a solvent mixture that consists of methanol and methylene chloride, is treated with activated carbon, and then is

filtered through a pressure filter with silica gel as a column material and the amount of silica gel is 3x the amount relative to the starring material, and the thus obtained pure rac-l-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-l-yl}-2,2-diphenylethan-l-one fumarate (V) is crystallized at 0°C from methanol.
2. Process as claimed in claim 1, wherein acetone is used as a solvent.
3. Process as claimed in claim 1, wherein the reaction is performed in a temperature range of 35 to 60°C.
4. Process as claimed in claim 1, wherein the amount of silica gel is 3x the amount relative to the starting material.
5. Process as claimed in claim 1, wherein the temperature in the crystallization in process stage (d) is 0°C.

Documents:

4595-DELNP-2005-Abstract-(08-10-2008).pdf

4595-DELNP-2005-Abstract-(18-05-2009).pdf

4595-delnp-2005-abstract.pdf

4595-DELNP-2005-Claims-(08-10-2008).pdf

4595-DELNP-2005-Claims-(18-05-2009).pdf

4595-delnp-2005-claims.pdf

4595-DELNP-2005-Correspondence-Others-(08-10-2008).pdf

4595-DELNP-2005-Correspondence-Others-(12-02-2009).pdf

4595-DELNP-2005-Correspondence-Others-(18-05-2009).pdf

4595-delnp-2005-correspondence-others.pdf

4595-DELNP-2005-Description (Complete)-(08-10-2008).pdf

4595-DELNP-2005-Description (Complete)-(18-05-2009).pdf

4595-delnp-2005-description (complete).pdf

4595-delnp-2005-form-1.pdf

4595-delnp-2005-form-18.pdf

4595-DELNP-2005-Form-2-(18-05-2009).pdf

4595-delnp-2005-form-2.pdf

4595-DELNP-2005-Form-3-(12-02-2009).pdf

4595-delnp-2005-form-3.pdf

4595-delnp-2005-form-5.pdf

4595-DELNP-2005-GPA-(08-10-2008).pdf

4595-delnp-2005-gpa.pdf

4595-delnp-2005-pct-210.pdf

4595-delnp-2005-pct-301.pdf

4595-delnp-2005-pct-304.pdf

4595-DELNP-2005-Petition-137-(12-02-2009).pdf

4595-DELNP-2005-Petition-138-(12-02-2009).pdf


Patent Number 235780
Indian Patent Application Number 4595/DELNP/2005
PG Journal Number 36/2009
Publication Date 04-Sep-2009
Grant Date 26-Aug-2009
Date of Filing 10-Oct-2005
Name of Patentee SCHERING AKTIENGESELLSCHAFT
Applicant Address MULLERSTRASSE 178, 13353 BERLIN, GERMANY.
Inventors:
# Inventor's Name Inventor's Address
1 HILMAR WEINMANN HEINRICH-HEINE STRASSE 72, 16548 GLIENICKE, GERMANY.
2 MATTHIAS SCHNEIDER OSNABRUCKER STRASSE 30, 10589 BERLIN, GERMANY
3 MICHAEL GOTTFRIED PAUL-ROBESON STRASSE 42, 10439 BERLIN, GERMANY.
PCT International Classification Number C07D 215/20
PCT International Application Number PCT/EP2004/004277
PCT International Filing date 2004-04-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 103 21 255.8 2003-05-06 Germany