Isosulfan blue, its crystalline form and process for preparation thereof

Abstract

Provided is an improved process for the preparation N-[4-[[4-(diethyl amino) phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium inner salt sodium salt (Isosulfan blue) of formula I. It also relates to highly pure novel crystalline form of Isosulfan blue hydrate and its process for the preparation thereof. It also relates to an improved process for the preparation of Isosulfan blue sodium hydrate having not more than 0.2% of desethyl impurity of formula A. ##STR00001##

Claims

1. A hydrate of Isosulfan blue sodium of formula I ##STR00022## comprising metal impurities of lead, arsenic and chromium, wherein lead is present at less than 2 ppm, arsenic is present at less than 3 ppm, and chromium is present at less than 50 ppm.

2. A Crystalline Isosulfan blue hydrate characterized by X-ray powder diffraction (XRPD) pattern comprising one or more of the reflections at 4.38, 14.64, 15.84, 16.14, 19.49, 22.25, 22.60 and 24.730.2 degrees 2 theta (2).

3. The crystalline Isosulfan blue hydrate as claimed in claim 2, further characterized by X-ray powder diffraction (XRPD) pattern comprising of the reflections at 6.51, 8.80, 11.69, 12.66, 12.90, 13.53, 17.05, 17.68, 18.20, 18.79, 20.29, 21.27, 23.01, 23.92, 25.49, 26.01, 26.78, 27.97, 28.66, 29.29 and 30.580.2 degrees 2 theta (2).

Description

BRIEF DESCRIPTION

(1) Some of the embodiments will be described in detail, with references to the following Figures, wherein like designations denote like members, wherein:

(2) FIG. 1: Represents characteristic X-ray powder diffraction (XRPD) pattern of crystalline form of Isosulfan blue (I) hydrate;

(3) FIG. 2: Represents characteristic TGA thermogram of crystalline form of Isosulfan blue (I) hydrate; and

(4) FIG. 3: Represents HPLC chromatogram of desethyl impurity of formula A.

DETAILED DESCRIPTION

(5) The following relates to an improved process for the preparation of Isosulfan blue of formula I in significantly high yield and substantially pure form. The following is schematically represented in Scheme-3 as follows:

(6) ##STR00010##

(7) In one aspect embodiments of the present invention provides a process for preparation of N-[4-[[4-(diethyl amino) phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium inner salt sodium salt (Isosulfan Blue) of formula I comprising the steps of: (a) sulphonation of Orthochloro benzaldehyde compound of formula II using fuming sulphuirc acid (Oleum) to obtain 4-chloro-3-formylbenzenesulfonic acid compound of formula III;

(8) ##STR00011## (b) conversion of 4-Chloro-3-formyl-benzenesulphonic acid compound of formula III to 1-formyl benzene-2,5-disulphonic acid disodium salt compound of formula IV by treatment with alkali metal sulphite;

(9) ##STR00012## (c) condensation of 1-formyl benzene-2,5-disulphonic acid disodium salt compound of formula IV with N,N-diethyl aniline of formula V in presence of hydrochloric acid to obtain a 4-[Bis[4-(diethylamino)phenyl]methyl]benzene-2,5-disulphonic acid compound of formula VI; optionally purifying the crude intermediate from a mixture of solvents;

(10) ##STR00013## (d) oxidizing 4-[Bis[4-(diethylamino) phenyl]methyl]benzene-2,5-disulphonic acid of formula VI with a suitable oxidizing agent in presence of inorganic acid to obtain Isosulfan blue of formula VII; optionally purifying crude compound by column chromatography;

(11) ##STR00014## (e) optionally purifying the crude Isosulfan blue of formula VII by recrystallizing from suitable solvents to provide highly pure Isosulfan blue of formula I.

(12) ##STR00015##

(13) Wherein, in step a) 20-25% of fuming sulphuric acid is used as a sulphonating agent and the sulphonating reaction was carried out at 1.4 equivalents of 20-25% fuming sulphuric acid.

(14) In step b) the suitable reagent alkali metal sulphite is selected from the group comprising sodium sulphite, potassium sulphite, Iron sulphite, zinc sulphite, copper sulphite, or the like; in one embodiment the alkali metal sulphite used is sodium sulphite. The solvent is selected from alcohols comprising ethanol, methanol, propanol, isopropanol and water or mixtures thereof.

(15) In step c) the reaction was carried out with 0.7 to 1.0 V of N,N-diethyl aniline in presence of hydrochloric acid.

(16) In step d) the suitable oxidizing reagent is either potassium dichromate or sodium dichromate or zinc dichromate or pyridinium dichromate; the suitable acid used is sulphuric acid; suitable solvents used for the purification of Isosulfan blue crude is selected from the group methanol, acetone, dichloromethane, or the mixture thereof.

(17) In step e) Isosulfan blue obtained in the above process is further purified from the solvents selected from group comprising alcohols like methanol, ethanol, isopropyl alcohol; water; acetonitrile; tetrahydrofuran; acetone; ethyl acetate; dichloromethane or mixtures thereof.

(18) A preferred embodiment of the present invention provides a process for the preparation of Isosulfan blue of formula I, comprising the steps of: (a) sulphonating Orthochloro benzaldehyde compound of formula II with 1.4 equivalents of 20-25% Oleum at 10-15 C. to obtain 4-Chloro-3-formyl-benzenesulphonic acid of formula III; (b) conversion of 4-Chloro-3-formyl-benzenesulphonic acid of formula III to 1-formyl benzene-2,5-disulphonic acid disodium salt of formula IV by treatment with sodium sulphite and sodium hydroxide at temperature ranging 85-110 C.; (c) condensation of 1-formyl-benzene-2,5-disulphonic acid disodium salt of formula IV with N,N-diethyl aniline of formula V in presence of hydrochloric acid to obtain a 4-[Bis[4-(diethylamino)phenyl]methyl]benzene-2,5-disulphonic acid of formula VI; optionally the obtained product is further purified by treatment with base followed by converting into free base to get pure compound VI; (d) oxidation of 4-[Bis[4-(diethylamino) phenyl]methyl]benzene-2,5-disulphonic acid of formula VI using potassium dichromate in presence of sulphuric acid and solvent to obtain Isosulfan blue of formula VII; optionally the obtained crude is further purified by Column chromatography using dichloromethane and methanol to obtain pure Isosulfan blue; (e) The final step involves optional purification of compound of formula VII by recrystallizing from methanol and Isopropyl alcohol to provide highly pure Isosulfan blue of formula I.

(19) In one aspect embodiments of the present invention provides a purification process to produce of Isosulfan blue devoid of the below impurity identified at RRT 0.9 by HPLC analysis.

(20) ##STR00016##

(21) The HPLC chromatogram of desethyl impurity of formula A is represented in FIG. 3.

(22) In another aspect Isosulfan blue obtained in embodiments of the present invention is having desmethyl impurity of formula A level less than 0.2% and also below 0.1%. Another aspect of embodiments of the invention pertains to method of purification of Isosulfan blue to control desethyl impurity at RRT 0.9 (HPLC) by column chromatography.

(23) The purification is carried out using 100-500 (like 100-200 or 200-400 or 230-400 or 200-425) mesh silica gel and an eluent is selected from the solvent from polar aprotic solvent such as dichloromethane, acetonitrile, methanol, ethanol and the mixtures thereof.

(24) Optionally Isosulfan blue obtained in the above column purification is further purified to remove other process related impurities as described herein.

(25) Isosulfan blue thus obtained in the above process is further purified by slurring in acetone followed by recrystallization from the mixture of polar protic solvents.

(26) In one aspect polar protic solvents used for the purification of Isosulfan blue after column is selected from methanol, ethanol, propanol, isopropyl alcohol and tertiary butyl alcohol.

(27) Embodiments of the present invention provides a process for the purification of Isosulfan blue comprising the steps of; (a) suspending crude Isosulfan blue in suitable solvents like methanol, ethanol, isopropanol, n-butanol, acetone, diethyl ether, Isopropyl ether, dichloromethane, acetonitrile, acetic acid and tetrahydrofuran, toluene, cyclohexane solvents or mixtures thereof; (b) stirring the solution for 1-2 hrs at 25-30 C.; (c) filtering the solution mass through 0.2-micron filter at 25-30 C.; (d) distilling off the filtrate under vacuum below 50 C.; (e) cooling the crude to 25-30 C. and adding solvents like methanol, ethanol, isopropyl alcohol, n-butanol, acetone, diethyl ether, isopropyl ether at 25-30 C.; (f) stirring for 2-3 hrs at 25-30 C.; (g) filtering the solid under vacuum at below 30 C.; and (h) drying the solid under vacuum below 50 C.

(28) Isosulfan blue obtained by the above purification is having moisture content less than 10%.

(29) Isosulfan blue obtained by the above purification is having moisture content less than 8%.

(30) Isosulfan blue obtained by the above purification is having moisture content less than 6%.

(31) Isosulfan blue obtained by the above purification is having moisture content less than 4%.

(32) The preparation or purification process of embodiments of the present invention provides Isosulfan blue of formula I, which comprises metal contents i.e lead level less than 2 ppm, arsenic level less than 3 ppm and chromium level less than 50 ppm.

(33) The process of embodiments of the present invention is the only one which gives Isosulfan blue sodium comprising impurity level less than 3% organic impurities, less than 2% impurities and less than 1% of impurities and total metal impurities less than 20 ppm.

(34) Isosulfan blue obtained by the purification process of embodiments of the present invention is having purity of greater than 98%, greater than 99% and desethyl impurity less than 0.2% and also less than 0.1%.

(35) The present inventors also found that the crystalline form of Isosulfan blue exists as further hydrated forms by exposing Isosulfan blue sodium at ambient temperature having a relative humidity 50-75% with increase in the moisture content from 10 to 15%. Ambient temperature means a temperature from 15 to 30 C., also from 25 to 30 C.

(36) In one embodiment of the invention Isosulfan blue obtained in the above process is crystalline form of Isosulfan blue hydrate.

(37) In one aspect of embodiments of the invention, a crystalline polymorphic form of Isosulfan blue hydrate is reported, whose X-ray powder diffraction (XRPD) pattern is represented by FIG. 1 and XPRD values are tabulated in Table 1.

(38) The crystalline polymorphic form of Isosulfan blue hydrate may produce an X-ray diffraction pattern comprising one or more of the following reflections at 4.38, 14.64, 15.84, 16.14, 19.49, 22.25, 22.60, 24.730.2 degrees 2 theta (2) or that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections at 6.51, 8.80, 11.69, 12.66, 12.90, 13.53, 17.05, 18.20, 18.79, 20.29, 21.27, 23.01, 23.92, 25.49, 26.01, 26.78, 27.97, 28.66, 29.29 and 30.580.2 degrees 2 theta (2) or that produces an X-ray powder diffraction pattern comprising the 2 theta values as tabulated in Table-1.

(39) The crystalline polymorphic form of Isosulfan blue hydrate may also be identified by the TGA thermogram as depicted in FIG. 2.

(40) Isosulfan blue obtained by the process of embodiments of the present invention is analysed by TGA and XRPD. The XRPD data of the crystalline form of Isosulfan blue hydrate obtained is tabulated in below table-1:

(41) TABLE-US-00001 TABLE 1 X-Ray powder diffraction (XRPD) data of crystalline polymorphic form of Isosulfan blue hydrate S. No. 2 Theta.sup. d value Angstrom Relative intensity % 1. 4.38 20.12 100 2. 6.51 13.56 25.9 3. 8.80 10.03 31.2 4. 11.69 7.55 29.8 5. 12.66 6.98 29.4 6. 12.90 6.85 24.8 7. 13.53 6.53 24.4 8. 14.64 6.04 80.2 9. 15.84 5.58 76 10. 16.14 5.48 59.7 11. 17.05 5.19 26.9 12. 17.68 5.00 94 13. 18.20 4.86 37.4 14. 18.79 4.71 36.8 15. 19.49 4.54 44.7 16. 20.29 4.37 35.7 17. 21.27 4.17 18.7 18. 22.25 3.99 48.7 19. 22.6 3.93 49 20. 23.01 3.86 35.9 21. 23.92 3.71 26.5 22. 24.73 3.59 47.6 23. 25.49 3.49 27.7 24. 26.01 3.42 22.7 25. 26.78 3.32 21.9 26. 27.97 3.18 17.7 27. 28.66 3.11 14.9 28. 29.29 3.04 22.9 29. 30.58 2.92 14.9

(42) The following examples further illustrate embodiments of the present invention, but should not be construed in any way as to limit its scope.

Example 1: Preparation of 4-Chloro-3-Formyl-Benzenesulfonic Acid of Formula III

(43) ##STR00017##

(44) 100 g of 2-chlorobenzaldehyde was charged to 4 volumes of 20-25% of fuming sulphuric acid over a period of 1-2 hrs at 10-15 C. stirred the reaction mass temperature for 30-40 minutes at 10-15 and gradually raised the temperature to 25-30 C. and then to 65-70 C. The obtained reaction mass was further stirred for 5-6 hrs at 65-70 C. and quenched in cold water. To this 300 g of sodium chloride was added and stirred for 3-4 hrs at 25-30 C. Filtered the precipitated solid and dried under vacuum at below 75 C. Yield: 50% Purity: NLT 95%

Example 2: Preparation of Sodium 2-Formylbenzene-1,4-Disulfonate

(45) ##STR00018##

(46) 10 g of 4-Chloro-3-formyl-benzenesulfonic acid was dissolved in 25 ml of water and adjusted pH of the reaction mass to 9-10.5 with aqueous Sodium hydroxide solution. To this, 2.3 g of Sodium sulphite and 4 ml of water were added and heated to 100-105 C. Stirred the reaction mass for 12-14 hrs at 100-105 C. Water was distilled off and the residue was stripped off with 20 ml of Isopropyl alcohol. The reaction mixture was stirred in 300 ml of Isopropyl alcohol at 20-30 min, then cooled to 10-15 C., stirred for 1 hr, filtered, washed with of Isopropyl alcohol and dried under vacuum at temperature below 50 C. to get Sodium 2-formylbenzene-1,4-disulfonate. Purity: NLT 85%

Example 3: Preparation of 2-(Bis(4-(Diethylamino)Phenyl)Methyl)Benzene-1,4-Disulfonic Acid

(47) ##STR00019##

(48) 90 ml of N,N-diethyl aniline was added to 100 g of Sodium2-formylbenzene-1,4-disulfonate at 25-30 C. To this 33-66 ml of Concentrated Hydrochloric acid was added over a period of 20-30 min. The reaction mixture was heated to 100-105 C. and maintained for 12-14 hrs. After reaction completion, cooled to 25-30 C. then to 0-5 C. Charged 50 ml of Isopropyl alcohol, stirred for 20-30 min, filtered and washed with chilled (0-5 C.) Isopropyl alcohol. Slurried above solid in Isopropyl alcohol and added 400 ml of Ethanol and cooled to 0-5 C. The pH was adjusted between 11.5-12.0 using aqueous Sodium hydroxide solution, stirred for 1 hr, filtered and washed with 200 ml of chilled (0-5 C.) Ethanol. Distilled off the filtrate and charged 100 ml of water and cooled to 0-5 C. The pH was adjusted between 1-2 using conc. Hydrochloric acid and maintained for 4-5 hrs, filtered, washed with 200 ml chilled water and dried under vacuum at temperature below 60 C. to get 2-(Bis(4-(diethylamino)phenyl)methyl)benzene-1,4-disulfonic acid of formula VI. PurityNLT 96%; Yield 25%

Example 4: Preparation of Isosulfan Blue Using Potassium Dichromate as Oxidizing Agent

(49) ##STR00020##

(50) To 100 g of 2-(Bis(4-(diethylamino)phenyl)methyl)benzene-1,4-disulfonic acid, 50 ml of methanol, 100 ml of water and 15 g of Sodium hydroxide were added at 25-30 C. Cooled to 0-5 C., 25 g of Potassium dichromate was added over a period of 20-30 min, stirred for 15-20 min, 200 ml of 25% aqueous sulphuric acid solution was added over a period of 30-40 min. The reaction mixture temperature was raised to 25-30 C., stirred for 10-12 hrs and charged 500 ml of water, cooled the reaction mixture to 0-5 C. and adjusted pH of the reaction mass between 8.5-9.0 using 600 ml of aqueous sodium hydroxide solution, 25 g of potassium dichromate was added over a period of 20-30 min, stirred for 15-20 min, 200 ml of aqueous 25% sulphuric acid solution was added over a period of 20-30 min. The reaction mixture temperature was raised to 25-30 C. and stirred for 4-5 hrs. After reaction completion, cooled to 0-5 C., pH was adjusted between 9.5-10.0 using 300 ml of 20% aqueous Sodium hydroxide solution. The reaction mixture temperature was raised to 25-30 C. and stirred for 60-90 min, filtered through hyflo and washed with methanol. Filtrate was distilled off under vacuum below 70 C., then charged 1000 ml of ethanol. Stirred the reaction mass for 20-30 min, filtered and washed with chilled (0-5 C.) ethanol followed by chilled (0-5 C.) methanol.

(51) Purification of Isosulfan blue to remove desethyl impurity: Filtrate was distilled off to half of its total volume at below 65 C., cooled to 25-30 C., the obtained crude (purity65%) was impregnated with 500 g of (230-400 mesh) Silica gel and dried at NMT 55 C. Column was packed with (230-400 mesh) Silica gel and loaded the impregnated crude, eluted the column using dichloromethane and methanol gradient mixture as eluent. Compound was eluted in 8-12% of methanol in dichloromethane, collected the fractions distilled off the solvent from pure fractions under vacuum at 40 C. The obtained crude was slurred in acetone for 1 hr, filtered and washed with acetone. The obtained compound was dried under vacuum below 50 to get Isosulfan blue sodium. Purity NLT 98%; yield 30%.

Example 5: Purification of Isosulfan Blue (I)

(52) ##STR00021##

(53) To a 30 g of Isosulfan blue sodium, 300 ml of methanol was added and stirred for 1 hr at 25-30 C. Filtered the reaction mixture through 0.2 micron filter and distilled off the solvent under vacuum below 50 C. Cooled the crude mass to 25-30 C. and stirred for 2-3 hrs in Isopropyl alcohol. Filtered and dried the solid below 50 C. to get Isosulfan blue sodium. Purity NLT 99.9%; yield 90%.