FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Isosulfan Blue of formula I.

BACKGROUND OF THE INVENTION

Isosulfan Blue is chemically known as N-[4-[[4-(diethylamino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1 -ylidene]-N-ethylethanaminium hydroxide, inner salt, sodium salt. Isosulfan blue is a triarylmethane dye used as a contrast agent for the delineation of lymphatic vessels and is particularly useful as a cancer diagnostic agent. It is a 2,5-isomer of sulfan blue or patent blue. Isosulfan blue is an active pharmaceutical ingredient used in Lymphazurin® blue dye pharmaceutical dosage form, available as 1% (10 mg/ml) 5 ml solution in phosphate buffer for injection. It has been approved in a procedure called "mapping of the sentinel lymph nodes".

US 1,531,507 discloses a process for the preparation of Isosulfan Blue by sulphonating orthochlorobenzaldehyde (II) using oleum (26% and oleum 65%) followed by addition of sodium carbonate to produce sodium salt of 2-chlorobenzaldehyde-5-sulfonic acid (III), which is further reacted with sodium sulphite to produce benzaldehyde-2,5-disulfonic acid sodium salt (IV). Compound (IV) is condensed with alkylated arylamine to produce isoleuco compound (V), which is oxidized to produce Isosulfan Blue (I).

The process is as shown in Scheme-I below:

US 7,534,911 discloses a process, wherein condensing benzaldehyde-2,5-disulfonic acid sodium salt (IV) with diethylaniline to produce disodium salt of isoleuco compound (Va).

Compound (Va) is oxidized using ammonium dichromate to produce Isosulfan blue sodium (la).

The process is as shown in Scheme-II below:

Scheme -II
US 7,662,992 also discloses a process, wherein oxidation of isoleuco acid (V) is carried out using 2 to 3 equivalents of silver oxide to produce Isosulfan blue (I), which is further treated with sodium solution to produce Isosulfan blue sodium (la). The process is as shown in Scheme-Ill below:

Scheme -III

The major disadvantage with the above prior-art processes is that the intermediate compound (III), which is not pure and contaminated with undesired impurities such as inorganic salts and is carried forward, as impurities in the finished product Isosulfan Blue (I). Removal of these impurities in the final stage is very difficult and requires repeated crystallizations, which results in the low yield of Isosulfan Blue (I) and hence is not suitable for industrial scale operations.

Another major disadvantage with above processes is that during oxidation unwanted des ethyl impurity of formula (VI) is generated along with desired compound of formula (I), which is difficult to remove using any of the crystallization methods.

Hence, there is a need to have simple, easy to handle and cost effective process for the preparation of Isosulfan Blue with high purity.

The present invention is directed towards a process for the preparation of pure Isosulfan Blue, wherein 2-chlorobenzaldehyde-5-sulfonic acid (III) is purified and used in the next step.

The present invention is also directed towards a process for the preparation of pure Isosulfan Blue, wherein Isosulfan Blue (I) is purified by using column chromatography.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Isosulfan Blue (I) with high purity on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of 2-clorobenzaldehyde-5-sulfonic acid of formula (Ilia), which comprises: (i) reacting orthochlorobenzaldehyde (II),

with a sulfonating agent to produce compound of formula (Ilia), (ii) purifying the compound of formula (IIIa), and (iii) isolating pure compound of formula (Ilia).

In another embodiment, the present invention provides a process for the preparation of Isosulfan Blue using the pure 2-clorobenzaldehyde-5-suIfonic acid of formula (Ilia).

In another embodiment, the present invention provides purification of Isosulfan Blue (I);

which comprises; (i) purifying Isosulfan Blue (I) using Column chromatography, (ii) isolating pure Isosulfan Blue (I), and (iii) optionally, converting pure Isosulfan Blue in to its sodium salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of 2-clorobenzaldehyde-5-sulfonic acid of formula (IIIa).

The process comprises, reacting 2-chlorobenzaldehyde (II) with a sulfonating agent to produce 2-chlorobenzaldehyde-5-sulfonic acid (IIIa).

The reaction is carried out at a temperature of about 10 to 30°C for a period of about 1 to 4 hrs, preferably 1 hr. After addition of sulfonating agent selected from 20% fuming sulfuric acid (based on sulfur trioxide molecular weight), sulfur trioxide, oleum, chlorosulfonic acid (SO3 plus HC1), sulfamic acid, metallic sulfites, sulfur dioxide with chlorine, sulfur dioxide with oxygen, sulfomethylating agents (hydroxyl- and aminomethanesulfonates), sulfoetylating agents (hydroxyl-, chloro-, and methylaminoethanesulfonates; ethylene sulfonic acid), the temperature of the reaction is raised up to 50°C to 100° C, preferably at 70° C. Thereafter, the reaction mixture is poured into crushed ice, followed by solid sodium chloride is added in lots wise to the acidic solution to precipitate 2-chlorobenzaldehyde-5-sulfonic acid (IIIa) is isolated by filtration.

2-Chlorobenzaldehyde-5-sulfonic acid (IIIa) is suspending/dissolving in an alcoholic solvent selected from methanol, ethanol, isopropanol, n-butanol or tert-butanol. The purification step is carried out at a temperature of 15°C to 60°C, preferably 45-50°C. The inorganic salts are filtered through hyflo and the filtrate is evaporated under reduced pressure. The pure compound (IIIa) is isolated by conventional techniques such as filtration and dried the product.

In another embodiment, the present invention also relates to the use of pure 2-chlorobenzaldehyde-5-sulfonic acid (IIIa), prepared by the present invention in the preparation of Isosulfan blue sodium.

The process comprises, reacting 2-chlorobenzaldehyde-5-sulfonic acid (Ilia) with sodium sulfite and sodium bisulfite or mixtures thereof to produce benzaldehyde-2,5-disulfonic acid, sodium salt (Crude) (IV).

Optionally the reaction is carried out under pressure at a temperature of 150°C to 190°C, preferably, at 170°C to 180°C. Thereafter, cooling the reaction mixture and a solvent selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol is added. The reaction mass is filtered to remove the inorganic salts. The filtrate is concentrated to produce benzaldehyde-2,5-disulfonic acid, sodium salt (IV). Compound (IV) is purified by suspending in a solvent selected from N,N-dimethylformamide and preferably at 110° to 115°C, followed by filtration through hyflo and the filtrate is precipitated using a solvent selected from methylene chloride to produce pure benzaldehyde-2,5-disulfonic acid, sodium salt (IV).

The pure benzaldehyde-2,5-disulfonic acid, sodium salt (IV) is condensed with N,N-diethylaniline in presence of an acid selected from glacial acetic acid, followed by addition of a solvent selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol to produce isoleuco acid (V).
Oxidation of isoleuco acid (V) is carried out with an oxidizing agent selected from pyridinium chlorochromate, pyridinium dichromate, potassium dichromate, ammonium dichromate, or manganese dioxide, hydrogen peroxide, lead peroxide, silver oxide to produce Isosulfan Blue (I).

The reaction is carried out in a solvent selected from water at a temperature of 25 to 50°C. During reaction, pH is maintained at ± 0.1 to 2.0 using an acid selected from phosphoric acid, hydrochloric acid and sulfuric aid. The reaction mixture is filtered through hyflo to remove the insoluble matter from the reaction mass. The resulting reaction mass containing Isosulfan Blue (I) is purified by conventional methods such as evaporation of solvent or by precipitating by addition of a solvent.

In 'another embodiment, the present invention also relates to a process for the purification of Isosulfan Blue (I) using column chromatography selected from Preparative HPLC.

The purification is carried out using Cig reverse phase silica gel and an eluent is selected from a solvent selected from a polar aprotic solvent such as acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide and water or mixtures thereof. The purified Isosulfan Blue (I) having HPLC chromatographic purity of about 99.0%.

The pure Isosulfan Blue (I) is converted to its sodium salt by treating with a sodium ion source, followed by crystallization to produce to Isosulfan blue sodium slat (la) with a chromatographic purity 99 to 99.9 %.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE: 1

Process for the Preparation of Isosulfan Blue sodium

Step 1: Preparation of 2-chlorobenzaldehyde-5-sulfonic acid (IIIa):

20% Fuming sulfuric acid (113.82 g, based on sulfur trioxide molecular weight, 569 ml) was charged and cooled to 15-20°C. 2-chlorobenzaldehyde (100 g, 0.71 moles) was added drop wise to the reaction mass at 15-20°C over a period of 60 min. The reaction mixture was heated to 70°C and stirred at 70°C for 3 h. Thereafter, the reaction mixture was poured into crushed ice (1200 g) and stirred. Solid sodium chloride (500 g) was added in lots wise to a stirred acidic solution to precipitate a light yellow colored solid. The solid was collected by filtration and washed with diethyl ether to afford 2-chlorobenzaldehyde-5-sulfonic acid (crude) (400 g).

Purification of 2-chlorobenzaldehyde-5-sulfonic acid (IIIa):

2-Chlorobenzaldehyde-5-sulfonic acid (crude) (400 g) was suspended in methanol (2000 ml) at 25-30°C. The reaction mixture was stirred for 1 h at 50-55°C. The inorganic salts were filtered through hyflo and the filtrate was evaporated under reduced pressure to obtain a solid residue. The solid residue was treated with methanol, collected by filtration to give 2-chlorobenzaldehyde-5-sulfonic acid (140 g, 89.23%) with chromatographic purity 99.76% performed by HPLC.

Step 2: Preparation of benzaldehyde-2,5-disulfonic acid, sodium salt (IV):

2-Chlorobenzaldehyde-5-sulfonic acid (100 g, 0.454 moles), Na2SO3 (131.43 g, 1.043 moles) and NaHSO3 (13.20 g, 0.127 moles) were dissolved in water (800 ml). The solution was charged into autoclave with stirring and heating. The reaction mixture was stirred and heated at 170-180°C (generates -150 p.s.i. pressure) for 2 h. After cooling and releasing the pressure, the reaction mixture was poured into methanol (3200 ml) and stirred. The inorganic salts were removed by filtration. The filtrate was concentrated to give benzaldehyde-2,5-disulfonic acid, sodium salt (crude) (70 g).

Purification of benzaldehyde-2,5-disulfonic acid, sodium salt (IV):

Benzaldehyde-2,5-disulfonic acid, sodium salt (crude) (70 g) was suspended in N,N-dimethylformamide (595 ml) and stirred for 1 h at 110-115°C. The mixture was filtered through hyflo and the filtrate was precipitated using methylene chloride (1855 ml) to afford Benzaldehyde-2,5-disulfonic acid, sodium salt (20 g) with chromatographic purity 99.16% performed by HPLC.

Step 3: Preparation of N-4-[bis[4-(diethylamino)phenyl]methyl]benzene-2,5-disuiphonic acid (Isoleuco acid) (V):

Benzaldehyde-2,5-disulfonic acid, sodium salt (15 g, 0.0484 moles) and glacial acetic acid (240 ml) were charged. N,N-diethylaniline (15.15 g; 0.1016 moles) was added to the stirred mixture and reflux for 35-40 h. The reaction mass was cooled to room temperature. Thereafter, methanol (150 ml) was added, and then the solid was separated and collected by filtration. The collected solid was washed with methanol to obtain of Isoleuco acid (18 g, 68.18 %) with chromatographic purity 99.28% performed by HPLC.

Step 4: Preparation of N-[4-[[4-(diethylamino)phenyl](2,5-disuIfophenyl)-methylene]-2,5-cyclohexadien-l-ylidene]-N-ethylethanaminium inner salt (Isosulfan Blue) (I):

Isoleuco acid (15 g, 0.027 moles) was suspended in DM water. Manganese dioxide (5.97 g, 0.068 moles, 2.5 m. eq.) was added to the stirred suspension in one portion at room temperature. Phosphoric acid was added to lower the pH to 2.0, and stirred at room temperature for 4-5 h. The reaction mixture was filtered through hyflo to remove the insoluble matter from the reaction mass and the residue was washed with water. The compound was purified through column chromatography to yield Isosulfan blue (10 g, 66.93 %) with chromatographic purity 99.62% performed by HPLC.

Step 5: Preparation of N-[4-[[4-(diethylamino)phenyI](2,5-disulfophenyl)-methylene]-2,5-cyclohexadien-l-ylidene]-N-ethylethanaminium inner salt (Isosulfan Blue, Sodium salt) (la):

Isosulfan blue (5 g; 0.092 moles) was dissolved in DM water. Aqueous sodium bicarbonate solution was added drop wise to the reaction mixture to adjust pH to 8-8.5 and continued stirring at 20-25°C for 1 h. Acetone (210 ml) was added to the reaction mixture and stirred at 20-25°C for 2h. The crystallized product was filtered and the solid obtained was dried at 40°C to yield Isosulfan blue sodium slat (4g, 76.92%) with chromatographic purity 99.79% performed by HPLC.

WE CLAIM:

1. A process for the preparation of 2-clorobenzaldehyde-5-sulfonic acid (IIIa), with a sulfonating agent to produce compound of formula (IIIa), (ii) purifying the crude compound of formula (IIIa), and (iii) isolating pure compound of formula (Ilia).

2. A process according to claim 1, wherein the sulfonating agent comprises 20% fuming sulfuric acid (based on sulfur trioxide molecular weight), sulfur trioxide, oleum, chlorosulfonic acid (SO3 plus HC1), sulfamic acid, metallic sulfites, sulfur dioxide with chlorine, sulfur dioxide with oxygen, sulfomethylating agents (hydroxyl- and aminomethanesulfonates), sulfoetylating agents (hydroxyl-, chloro-, and methylaminoethanesulfonates; ethylene sulfonic acid).

3. The process according to claim 1, wherein the purification is carried out in presence of a solvent.

4. The process according to claim 3, wherein the solvent comprises methanol, ethanol, isopropanol, n-butanol or tert-butanol.

5. The process according to claim 1, wherein the pure 2-clorobenzaldehyde-5-sulfonic acid of formula (IIIa) is used in the preparation of Isosulfan Blue (I).

6. A process for the purification of Isosulfan Blue (I), which comprises;

(i) purifying Isosulfan Blue (I) by chromatography,

(ii) isolating pure Isosulfan Blue (I), and

(iii) optionally, converting pure Isosulfan Blue in to its sodium salt.

7. A process according to claim 6, wherein the chromatography comprises column chromatography.

8. A process according to claim 7, wherein the column chromatography comprises preparative HPLC with a C18 reverse phase silica gel using an eluent.

9. A process according to claim 8, eluent used in the chromatography comprises a solvent selected from a polar aprotic solvent such as acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide and water or mixtures thereof.

10. A process according to claim 6, wherein the pure Isosulfan Blue (I) is converted to its sodium salt by treating with a sodium ion source.