U.S. patent application number 11/747291 was filed with the patent office on 2008-11-13 for process for preparation of isosulfan blue.
This patent application is currently assigned to Apicore, LLC. Invention is credited to Ravishanker Kovi, Satyam Nampalli, Peter Xavier Tharial.
Application Number | 20080281127 11/747291 |
Document ID | / |
Family ID | 39970132 |
Filed Date | 2008-11-13 |
United States Patent
Application |
20080281127 |
Kind Code |
A1 |
Kovi; Ravishanker ; et
al. |
November 13, 2008 |
PROCESS FOR PREPARATION OF ISOSULFAN BLUE
Abstract
A process for the preparation of isosulfan blue (Active
Pharmaceutical Ingredient) is provided. A process is also provided
for preparation of the intermediate,
2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2),
used in the preparation thereof and a procedure for the isolation
of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula
(3). Also provided is a process for the preparation of an isoleuco
acid of formula (4), which upon mild oxidation gives rise to
isosulfan blue of pharmaceutical grade which can be used for
preparation of pharmaceutical formulations. The isolation and
purification procedures provided in the process provide
substantially pure isosulfan blue with HPLC purity 99.5% or
greater.
Inventors: |
Kovi; Ravishanker; (Monroe,
NJ) ; Nampalli; Satyam; (Belle Mead, NJ) ;
Tharial; Peter Xavier; (Piscataway, NJ) |
Correspondence
Address: |
KAPLAN GILMAN GIBSON & DERNIER L.L.P.
900 ROUTE 9 NORTH
WOODBRIDGE
NJ
07095
US
|
Assignee: |
Apicore, LLC
Somerset
NJ
|
Family ID: |
39970132 |
Appl. No.: |
11/747291 |
Filed: |
May 11, 2007 |
Current U.S.
Class: |
568/30 |
Current CPC
Class: |
C07C 303/22 20130101;
C07C 309/46 20130101; C07C 303/02 20130101; C07C 303/22 20130101;
C07C 309/52 20130101 |
Class at
Publication: |
568/30 |
International
Class: |
C07C 315/00 20060101
C07C315/00 |
Claims
1. A process of preparing N-[4-[[4-(diethyl
amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-
-ethylethanaminium, sodium salt comprising combining a suspension
of isoleuco acid of the formula ##STR00007## in a polar solvent
methanol with 2.0 to 3.0 equivalents of silver oxide.
2. The process according to claim 1 comprising sulfonation of
2-chlorobenzaldehyde to obtain 2-chlorobenzaldehyde-5-sulfonic acid
sodium salt of the formula ##STR00008## followed by nucleophilic
displacement of the chloride in 2-chlorobenzaldehyde-5-sulfonic
acid sodium salt with an alkali metal sulfite and bisulfite to
obtain benzaldehyde-2,5-disulfonic acid, disodium salt of the
formula ##STR00009## and condensing the benzaldehyde-2,5-disulfonic
acid, disodium salt of the formula (3) with N, N-diethylaniline
using urea and glacial acetic acid to provide isoleuco acid of the
formula (4).
3. A process of preparing 2-chlorobenzaldehyde-5-sulfonic acid,
sodium salt of formula (2) comprising reacting one equivalent of
2-chlorobenzaldehyde with 2 equivalents, based on SO.sub.3 content,
of 20% fuming sulfuric acid.
4. The process according to claim 3 comprising employing an
isolation medium comprising crushed ice and sodium chloride.
5. The process according to claim 2 of preparing free
benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula
##STR00010## wherein the alkali metal sulfite and bisulfite
comprise sodium sulfite and sodium bisulfite salts.
6. The process according to claim 5 wherein the reaction is carried
out in a pressure vessel at 170-180.degree. C. for 5 to 7
hours.
7. The process according to claim 6 wherein the reaction is carried
out under a pressure of 140 to 150 psi.
8. The process according to claim 2 comprising precipitating
inorganic salts which will hinder the rate of reaction using
methanol or one or more C.sub.14 lower alcohols.
9. The process according to claim 2 in which the
benzaldehyde-2,5-disulfonic acid disodium salt is purified by
extracting with a non-aqueous polar solvent followed by its
precipitation in a halogenated or non-halogenated non-polar solvent
which is miscible with the non-aqueous polar solvent.
10. The process according to claim 9 wherein the nonaqueous polar
solvent is N,N dimethylformamide and the nonpolar solvent is
dichloromethane.
11. A process of preparing isoleuco acid of the formula
##STR00011## comprising combining a benzaldehyde-2,5-disulfonic
acid, disodium salt of the formula (3) with N,N-diethylaniline, and
urea and glacial acetic acid.
12. The process according to claim 11 performed at reflux
conditions for 20-25 hours at 115 to 120.degree. C.
13. The process according to claim 11 comprising precipitating a
crude solid using methanol or a C.sub.14 lower alcohol.
14. The process according to claim 11 in which the crude solid is
further purified using water.
15. The process according to claim 1 comprising oxidation of
isoleuco acid of the formula (4) with 2.5 equivalents of silver
oxide in methanol, resulting in a reaction mass. and stirring the
reaction mass at 20 to 25.degree. C. for 12-14 hours, and filtering
the silver oxide to provide a filtrate.
16. The process according to claim 15 comprising filtering the
silver oxide, passing the filtrate through a bed of silica gel and
celite and passing the filtrate through a zeolite bed optionally
treated with an acid or base.
17. The process according to claim 16 further comprising passing
the filtrate through a 0.2 micron filtration unit.
18. The process according to claim 15 comprising precipitating the
filtrate using a non-polar solvent miscible with the filtrate.
19. The process according to claim 18 wherein the non-polar solvent
is isopropyl ether.
20. The process according to claim 1 comprising adjusting the
N-[4-[[4-(diethylamino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexa-
dien-1-ylidene]-N-ethylethanaminium to a pH greater than 6.0 using
an aqueous inorganic or organic derivative of sodium or a
combination thereof.
21. The process according to claim 20 wherein the pH is adjusted
using sodium bicarbonate solution.
22. The process according to claim 1 comprising recrystallization
of
N-[4-[[4-(diethylamino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexa-
dien-1-ylidene]-N-ethylethanaminium using a solvent selected from
the group consisting of a polar solvent, a non-polar solvent and a
combination thereof to afford HPLC purity greater than 99.5%.
23. The process according to claim 22 wherein the solvent is
selected from an aqueous acetone medium and 80% aqueous
isopropanol/acetone.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for the
production of isosulfan blue, and in particular, to a process for
the production of isosulfan blue in a substantially pure form.
BACKGROUND OF THE INVENTION
[0002] Isosulfan blue, having a chemical name, N-[4-[[4-(diethyl
amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-
-ethylethanaminium, sodium salt and the formula
##STR00001##
is a triarylmethane dye used as a contrast agent for the
delineation of lymphatic vessels and is particularly useful as a
cancer diagnostic agent. Also known chemically as sulfan blue or
patent blue, isosulfan blue is an active pharmaceutical ingredient
used in the Lymphazurin.TM. blue dye pharmaceutical dosage form,
available as 1% (10 mg/ml) 5 ml solution in phosphate buffer for
injection. It is commonly used in a procedure called "mapping of
the sentinel lymph nodes". It is an adjunct to lymphography for
visualization of the lymphatic system draining the region of
injection. It has been used with increasing frequency in localizing
sentinel lymph nodes in breast cancer patients. Isosulfan
blue-guided surgical removal of cancerous tissue has been on the
rise as it is cost effective and safer to use than technetium 99M
radioisotope-labeled sulfur colloid. Isosulfan blue is a structural
isomer of sulphan blue; both belong to the family of triarylmethane
dyestuffs. Generally, preparation of triarylmethane dyes involves
condensation of suitably substituted aryl aldehydes with 2
equivalents of alkyl-aryl amines giving rise to leuco-bases or
leuco-acids followed by oxidation. Although the literature is
replete with methods of preparing triarylmethane dyes, most of the
methods involve strong acids for condensation resulting in
leuco-bases or leuco-acids, hazardous oxidizing agents (lead oxide,
chloranil, iron phthalocyanine/oxone) for converting to
triarylmethane dyes, and crude methods (precipitation with sodium
sulfate) of purification. See for example U.S. Pat. Nos. 4,330,476,
4,710,322, 1,531,507, 5,659,053, 1,805,925, 2,422,445, 1,878,530
and 2,726,252. Prior art methods of isolation of the crude
leuco-acids or leuco-bases involve tedious
neutralization/basification with strong bases and typically using
the reaction mixtures in the oxidation step, giving rise to crude
triarylmethane dyes. The triarylmethane dyestuffs thus prepared are
used mainly for dyeing fabric, coloring paper, and printing inks.
The literature cites utilization of the same aforementioned
synthetic and isolation methods for the preparation of
diagnostically important dyes, such as isosulfan blue, sulphan blue
and patent blue V. See, Rodd's Chemistry of Carbon Compounds by S.
Coffey, 1974 2.sup.nd Edition, Volume III Part F, 110-133.
[0003] Therefore there is a need in the art for an improved method
in the process chemistry of isosulfan blue to be prepared in the
purest form which is suitable for large scale cGMP production for
its pharmaceutical formulation manufacturing.
SUMMARY OF THE INVENTION
[0004] It is therefore an object of the present invention is to
provide a simple, safe, cost-effective, time saving and reliable
process for the preparation of isosulfan blue in bulk scale and in
substantially pure form. "Substantially pure" is defined herein as
99.0% or greater.
[0005] Another object of the invention is to provide a simple,
cost-effective and reliable process for preparation of the
intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of
formula (2), required in the preparation of isosulfan blue. This
embodiment provides a process step that does not require tedious
neutralization with very large quantities of sodium carbonate and
effervescence, as is the case in prior art processes.
[0006] Another object of the invention is to provide a simplified
procedure for the isolation of benzaldehyde-2,5-disulfonic acid,
di-sodium salt of the formula (3) that does not include acidifying
the reaction mixture with concentrated sulfuric acid and boiling
until excess sulfurous acid is expelled, as is taught in the prior
art.
[0007] Yet another object of the invention is to provide a
procedure for obtaining the benzaldehyde-2,5-disulfonic acid,
sodium salt of formula (3) free of inorganic salts, which
essentially simplifies the isolation procedures to be implemented
during isolation of isoleuco acid.
[0008] Yet another, object of the invention is to provide a process
for the preparation of an isoleuco acid of formula (4), through the
urea derivative as an in-situ intermediate. The isoleuco acid of
formula (4) on further oxidation gives rise to the target compound,
isosulfan blue (5). Still another object of the invention is to use
very mild oxidation agent to avoid any over oxidized products and
also to improve the stability of the isosulfan blue under reaction
conditions.
[0009] According to this invention, there is provided a simple
procedure for the isolation of benzaldehyde-2,5-disulfonic acid,
isoleuco acid and isosulfan blue at acid stage and also at sodium
salt formation stage by incorporating crystallization techniques,
thereby avoiding distillation and other techniques using high
temperatures which jeopardize the compound stability during the
manufacturing process.
[0010] These and other aspects of the invention will be apparent to
those skilled in the art.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0011] In the following description, for purposes of explanation,
specific numbers, materials and configurations are set forth in
order to provide a thorough understanding of the invention. It will
be apparent, however, to one having ordinary skill in the art that
the invention may be practiced without these specific details. In
some instances, well-known features may be omitted or simplified so
as not to obscure the present invention. Furthermore, reference in
the specification to phrases such as "one embodiment" or "an
embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the invention. The
appearances of phrases such as "in one embodiment" in various
places in the specification are not necessarily all referring to
the same embodiment. In accordance with one embodiment the present
invention relates to a process for the preparation of isosulfan
blue.
Scheme
[0012] The following provides a process for the production of
isosulfan blue of formula (5):
##STR00002##
Experimental Procedures
[0013] In accordance with one embodiment of the present invention a
first step involves sulfonation of the commercially available
starting material of the formula (1) to
2-chlorobenzaldehyde-5-sulfonic acid sodium salt of the formula
(2).
##STR00003##
[0014] In one example, the sulfonation process involved reacting
one equivalent of the 2-chlorobenzaldehyde of formula (1) with 2.0
equivalents of 20% fuming sulfuric acid at 15.degree. C. to
70.degree. C. for 16 hrs. The reaction mixture was poured into
ice-water carefully followed by stirring with solid sodium chloride
resulting in a cream colored precipitate, which upon filtration,
washing with ether and drying afforded
2-chlorobenzaldehyde-5-sulfonic acid of the formula (2) in 86%
yield.
[0015] In accordance with one embodiment of the present invention,
a second step of the process involves nucleophilic displacement of
the chloride in 2-chlorobenzaldehyde-5-sulfonic acid sodium salt of
the formula (2) with an alkali metal sulfite/bisulfite such as
sodium sulfite/sodium bisulfite at elevated temperatures under
closed conditions.
[0016] In one example, this reaction was carried out in a Parr
pressure vessel equipped with overhead magnetic stirring.
2-Chlorobenzaldehyde-5-sulfonic acid (2), sodium sulfite (2.29
equivalents), sodium bisulfite (10% of sodium sulfite), and water
(3.45 mL/g) were charged into the Parr pressure vessel. The
reaction mixture in the vessel was stirred and heated at
170-180.degree. C. for 5-7 hours generating 140-150 psi
pressure.
[0017] The reaction mixture, after cooling, was poured into
methanol while stirring, so as to make 20% aqueous content of the
whole volume. This process ensured total precipitation of the
inorganic salts, which could be removed by filtration. The solvent
from the filtrate was removed under reduced pressure to obtain a
solid residue, which was triturated with methanol and filtered to
afford light yellow colored compound, benzaldehyde-2,5-disulfonic
acid, di sodium salt of the formula (3) in 93.9% yield.
[0018] In accordance with one embodiment a purification procedure
for removing the inorganic salts essentially involves dissolving
the crude solid in N,N dimethylformamide and stirring the contents
for 1-2 hours at ambient temperature followed by filtration. The
filtrate is precipitated by dichloromethane to afford the light
yellow colored compound, benzaldehyde-2,5-disulfonic acid disodium
salt of formula (3) with chromatographic purity NLT 99.0% and with
HPLC assay greater than 90% w/w.
##STR00004##
[0019] In accordance with one embodiment of the present invention,
a third step of the process involved condensing
benzaldehyde-2,5-disulfonic acid, disodium salt of the formula (3)
with N, N-diethylaniline to provide isoleuco acid of the formula
(4).
##STR00005##
[0020] In one example, pure isoleuco-acid of the formula (4) with
chromatographic purity greater than 98.0% was obtained in the solid
form out of the reaction mixture. A mixture of
benzaldehyde-2,5-disulfonic acid, disodium salt of the formula (3),
N,N-diethylaniline (2.2 equivalents), and urea (0.75 equivalents)
in glacial acetic acid was stirred and refluxed for 20-25 hrs. The
reaction progressed through the intermediate formation in-situ
which is a urea derivative of benzaldehyde-2,5-disulfonic acid
disodium salt. To the above cooled reaction mixture after 20-25 hrs
reflux, methanol was added to form a precipitate, which was
collected by vacuum filtration and washed with diethyl ether to
afford the isoleuco acid of the formula (4) in 56.8% yield.
[0021] The purification of isoleuco acid was carried out by
dissolving the crude solid in 5 volumes of water and stirred for
1-2 hours at ambient temperature and filtering the solid. The above
process was repeated twice before the final solid washed with
acetone to generate isoleuco acid of the formula (4) with
chromatographic purity greater than 99.5%.
[0022] In accordance with one embodiment of the present invention a
fourth step of the process involves conversion of the isoleuco acid
(4) to isosulfan blue of the formula (5) under conditions that
employ milder oxidizing agents with no strong acidic reagents and
are less hazardous than the prior art.
##STR00006##
[0023] In an example of the present inventive process, a suspension
of isoleuco acid of the formula (4) in methanol was stirred at room
temperature for 12-14 hrs with silver oxide (2.5 equivalents). The
blue colored reaction mixture was filtered through a pad of silica
gel and Celite followed by filtration through an acidic zeolite bed
and further through a 0.2 micron membrane filtration unit. The
filtrate was then precipitated with isopropyl ether at room
temperature to obtain crude isosulfan blue acid.
[0024] The isosulfan blue acid thus obtained was then purified by
recrystallization from aqueous isopropyl alcohol/acetone to afford
isosulfan blue acid of chromatographic purity NLT 99.5% performed
by High Performance Liquid Chromatography.
[0025] The final product of isosulfan blue sodium (formula 5) was
obtained when isosulfan blue acid was adjusted to a pH greater than
6.0 in aqueous acetone medium using sodium bicarbonate solution for
pH adjustment. The reaction mass was filtered to give isosulfan
blue sodium of formula (5) having purity greater than 99.5% by HPLC
and also free of silver with silver content estimated by Atomic
absorption spectrometer less than 20 ppm.
EXAMPLES
2-Chlorobenzaldehyde-5-sulfonic Acid, Sodium Salt of the Formula
(2)
[0026] 113.82 g (based on SO.sub.3 molecular weight, 569 mL) of 20%
fuming sulfuric acid (FSA) was charged into a 1 L three-neck flask
fitted with a dropping funnel, overhead stirrer, and thermometer.
The reaction mass was cooled to 15 to 20.degree. C. 100 g of
2-chlorobenzaldehyde of the formula (1) was added drop-wise to the
stirred and cooled FSA over a period of 40 minutes, so that the
temperature didn't rise above 20.degree. C. The reaction mixture
was stirred and heated at 70.degree. C. for 16 hours to obtain a
dark-brown colored reaction solution. The HPLC results indicated
the absence of the starting material. The dark-brown colored
reaction solution was carefully poured into a beaker containing
1200 g of crushed ice and stirred. 500 g of solid sodium chloride
was added portion wise to the stirred colored acidic solution to
precipitate a light-yellow colored solid. The light-yellow colored
solid was collected by vacuum filtration and washed with diethyl
ether to afford 150.0 g (86.92%) of 2-chlorobenzaldehyde-5-sulfonic
acid, sodium salt of the formula (2).
Benzaldehyde-2,5-disulfonic Acid, Sodium Salt of the Formula
(3)
[0027] 50 g (0.206 mol) of 2-chlorobenzaldehyde-5-sulfonic Acid,
Sodium Salt of the Formula (2), 59.75 g (0.474 mol, 2.3 eq.) of
Na.sub.2SO.sub.3 and 5.97 g (10% of Na.sub.2SO.sub.3) of
NaHSO.sub.3 were dissolved in 400 mL of water. The solution was
charged into a 600 mL capacity Parr pressure cylinder equipped with
stirring and heating. The reaction mixture was stirred (300-310
RPM) and heated at 180.degree. C. (generates .about.150 psi
pressure) for 5-7 hours. HPLC results indicate the absence of the
starting material. After cooling and releasing the pressure, the
reaction mixture was poured into 1600 mL of stirred methanol and
stirred for 15-30 minutes to precipitate the unwanted inorganic
salts. The inorganic salts were filtered off using a pad of Celite
and the filtrate evaporated under reduced pressure to obtain a
solid residue. The solid residue obtained was triturated with 200
mL methanol, collected by filtration and washed with ether to give
60 g (93.9%) of benzaldehyde-2,5-disulfonic acid, sodium salt of
formula (3).
Purification of Benzaldehyde-2,5-disulfonic Acid, Sodium Salt
Formula (3)
[0028] 60 g of crude benzaldehyde-2,5-disulfonic acid, disodium
salt prepared as per the procedure above was dissolved in 500 mL of
N,N-dimethylformamide and stirred for 2 hours at 20-25.degree. C.
The mixture was filtered through a buchner funnel and the filtrate
was precipitated using 1500 mL of dichloromethane to afford 20 g of
the light yellow colored compound, benzaldehyde-2,5-disulfonic acid
disodium salt of formula (3) with chromatographic purity NLT 99.0%
w/w.
Isoleuco Acid of the Formula (4)
[0029] 60 g of benzaldehyde-2,5-disulfonic acid sodium salt of
formula (3), 8.76 g of urea (0.75 eq), and 1000 mL of glacial
acetic acid were charged into a 3 L 3-neck flask fitted with a
mechanical stirrer and reflux condenser. 65.61 mL (2.2 eq) of
N,N-diethyl aniline was added to the stirred mixture and refluxed
for 20-25 hrs. When the HPLC results indicated the content of
starting material was less than 5%, the reaction mass was cooled to
room temperature. After cooling to room temperature, 600 mL of
methanol was added and the separated solid collected on a sintered
funnel by vacuum filtration. The collected solid washed with
methanol to obtain 55-60 g (56.8%) of crude isoleuco acid of the
formula (4).
Purification of Isoleuco Acid of Formula (4)
[0030] 50 g of crude isoleuco acid along with 250 ml of water was
charged into a 1 L 3-neck round bottom flask fitted with a
mechanical stirrer. The reaction mixture was stirred for 1 hour at
20-25.degree. C. The solid was filtered through a buchner
funnel.
[0031] The above process was repeated twice. The final product thus
obtained was then washed with 25 ml of acetone and then dried to
obtain 40-45 g of the desired isoleuco acid of formula (4).
Isosulfan Blue of the Formula (5)
[0032] 15 g (0.027 mol) of isoleuco acid of the formula (4) and 225
mL of Methanol were charged into a 1 L round bottomed flask and the
suspension was stirred. To the stirred suspension, 15.91 g (0.068
mol, 2.5 eq.) of silver oxide was added in one portion at room
temperature and stirred at room temperature for 12-14 hours. The
reaction mixture turned blue in color as the oxidation to the
desired product progressed. The HPLC results indicated the absence
of starting material. The blue colored reaction mixture was
filtered through a buchner funnel and the solid silver oxide
collected was taken into the reaction flask and the filtrate was
kept aside. 225 ml of methanol was added to the silver oxide taken
in the reaction flask and stirred at 20-25.degree. C. for 30
minutes and filtered through the buchner funnel. This silver oxide
washing procedure with methanol was carried out twice more.
[0033] The combined filtrates along with the initial filtrate were
then filtered through a bed of silica gel/celite (2 inch silica
gel/1 inch of celite) and finally the bed washed with 50 mL of
methanol.
[0034] The filtrate was then subjected to a filtration through an
acidic zeolite bed of 2 inch height (pH of the zeolite bed was
adjusted to acidic pH by using 0.1N hydrochloric acid aqueous
solution) followed by filtration through a 0.2 micron filtration
unit.
[0035] Isopropyl ether was added three times the volume of the
filtrate and the isosulfan blue acid was precipitated as a solid at
about 10 gram (68.8%) yield.
[0036] In order to prepare the Isosulfan blue sodium salt of the
formula (5), 10.0 g of the solid obtained above was dissolved in 30
mL deionized water. Saturated sodium bicarbonate solution was added
drop wise to adjust the pH to 8.0. To this 300 mL of acetone was
added and stirred at 20-25.degree. C. for 30 minutes. The
crystallized product was then filtered through a buchner funnel and
the solid thus obtained was dried at 40.degree. C. under vacuum to
obtain the isosulfan blue sodium salt of formula (5).
[0037] While the preferred embodiments have been described and
illustrated it will be understood that changes in details and
obvious undisclosed variations might be made without departing from
the spirit and principle of the invention and therefore the scope
of the invention is not to be construed as limited to the preferred
embodiment.
* * * * *