DE2046141A1 - Tricarbocyanine dyestuff mfr - using alkali alcoholate instead of sodium iodide to obtain iodine-free products - Google Patents

Abstract

Tricarbocyanine dyes made by reacting cycloammonium salts with acyl anilides of hexatrienyl cpds. separation of the dye obtd. by addition of ether and dissolving the raw product in methanol, are then reacted with an alkali alcoholate and ppted. with ehter. Pref. 1-2 mols. sodium methylate are used per mol. dyestuff and di-isopropyl ether is used for option. Esp. suitable for making a benzindole indocyanine dye (Indocyanine Green) used for photographic and diagnostic purposes where the presence of iodine e.g. in the thyroid gland test is undesirable.

Description

Process for the preparation of tricarbocyanine dyes Tricarbocyanines are valuable dyes because of their properties of absorbing infrared rays. They have therefore already been used for photographic and diagnostic purposes. A benzindole carbocyanine dye, namely indocyanine green of the formula, has become particularly well known as a diagnostic aid which is widely used in both circulatory and liver function diagnostics.

In the course of the known manufacturing processes (cf. in particular US Patents 2,895,955 and 2,251,286) for this compound is always sodium iodide added. The iodide anion is difficult to remove from the dye.

Treatment with silver chloride has been proposed. It succeeds However, in this way, the iodide content doesn't become significant under 5 ffi to lower. On the other hand, this iodide content is currently used in diagnostics extremely undesirable, because on the one hand annoying side effects can occur, and on the other hand, various other tests, e.g. 3. the thyroid test, not feasible.

It has now been found that, surprisingly, tricarbocyanine dyes can be used Can also be made åod-free if you use sodium iodide instead of sodium iodide Alkali alcoholates used.

The invention thus provides a method for producing Tricarbocyanine dyes by reacting cycloammonium salts with acylanilides of hexatrienyl compounds in alcoholic solution in the presence of basic condensation agents, Separation of the dye obtained by adding ether and dissolving the crude product in methanol, which consists in the fact that the methanolic solution thus obtained with an alkali alcoholate is added and the dye is then precipitated by adding ether.

Preferred alkali alcoholates are those of lower aliphatic alcohols with 1 - 4 carbon atoms derived compounds, i.e. in particular the methylates, ethylates, Propylates and butylates.

Preferred alkali metal is sodium, but also. Potassium or lithium is being brought up for consideration. The alcoholates are expediently approximately equimolecular Quantities too (based on the dye), optionally also in a slight excess. As a rule, about 1 to 2 moles of alkali metal alcoholate are used per mole of dye.

Due to the action of the alkali alcoholate after the condensation obtained crude color base into the monosodium salt transferred, whereby but the structure of the inner salt (betaine structure) is retained. It was not foresee that alkali alcoholates in one step will convert the crude parabase into a would transfer well-crystallizing salt. The NaI is added after known processes usually in two stages, since quaternization and salt formation apparently separated from a certain salting-out effect by which the dye is brought to crystallization.

It has also proven extremely beneficial instead of the ordinary ether (diethyl ether), which is usually used in the production of tricarbocyanine dyes Is used to use diisopropyl ether, especially in the last precipitation after treatment of the crude dye with alkali metal alcoholates, crystalline ones are better obtained Products that are then produced with a greater degree of purity than before. The usage of diisopropyl ether instead of diethyl ether is also on an earlier one Reaction stage of the synthesis of advantage, namely z. B. in the deposition of the condensation product by adding ether before dissolving the crude dye in methanol.

These benefits of using diisopropyl ether were not foreseeable.

Otherwise, the tricarbocyanine dyes are prepared after processes known from the literature. So z. B. also another purification be connected, such as a treatment of the dye obtained with a Solvents such as acetone, methyl ethyl ketone or ether. By boiling them out with them A further purification of the dyes can be carried out using solvents.

The new method is generally applicable, in particular to tricarbocyanine dyes with a betaine structure, the crude products of which are readily soluble in methanol. Significant are here in particular the benzindole carbocyanines.

Naturally, the new process is of particular interest in production of indocyanine green, as there is an iodine content in this dye when used in diagnostic applications Tests particularly bothers.

It is known that anhydro-2- (6-acetanilido-1,3,5-hexatrienyl) -3,3-dimethyl-1- (4-sulfobutyl) -4, 5-benzopseudoindolium hydroxide with anhydro-2,3,3-trimethyl-1 - (4-sulfobutyl) -4, 5-benzopseudoindolium hydroxide in the presence of a basic catalyst, in particular Triethylamine, implemented in alcoholic solution. After cooling the usually The refluxed solution is then added with ether, according to the invention the replacement of diisopropyl ether instead of diethyl ether is particularly advantageous is.

After decanting the supernatant solvent mixture The dye product obtained is then dissolved in methanol and, if appropriate, also filtered. Sodium methylate or another alkali metal alcoholate is added to this solution added and by stirring in ether, preferably diisopropyl ether, falls the indocyanine precipitate as a crystalline product. If desired, this product can still with z. B. acetone are boiled. After drying you get in very high Yield a very pure product with a melting point of 240-2450 example 2.33 kg (4.3 moles) of anhydro-2- (6-acetanilido-1 3,5-hexatrienyl) -3, 3-dimethyl-1 (4-sulfobutyl) -4,5-benzopseudoindolium hydroxide and 1.485 kg (4.3 moles) of 1- (4-sulfobutyl) -2,3,3-trimethyl-4,5-benzopseudoindolium hydroxide are with the addition of 0.44 kg (4.35 mol) of triethylamine in 13 l of ethyl alcohol 30 Heated to reflux for minutes. After cooling to 20-250, 30 liters of diisopropyl ether are added offset, whereby the raw color resin is deposited on the bottom. After decanting or The parabum resin is siphoned off in 25 l of methyl alcohol dissolved and the solution filtered.

A likewise filtered solution weighing 0.109 kg is added to this solution (4.73 moles) sodium in 3 liters of methyl alcohol added and the crystalline product is precipitated by stirring in 50 1 of diisopropyl ether. After filtration and drying the dye is boiled for 2 hours with 80 l of acetone and filtered hot. Man the indocyanine green obtained dries in vacuo at 500.

Yield: 3.05 kg, melting point 240-243o (decomp.), Corresponding to 91.5% of theory. Th.

Claims (6)

Claims fi) Process for the preparation of tricarbocyanine dyes by Implementation of cycloammonium salts with acylanilides of hexatrienyl compounds in alcoholic solution in the presence of basic condensation agents, separation of the obtained dye by adding ether and dissolving the crude product in methanol, characterized in that the methanolic solution thus obtained with a Alkali alcoholate is added and the dye is then precipitated by adding ether. 2. The method according to claim 1, characterized in that about 1-2 moles of alkali metal alcoholate are added per mole of dye. 3. The method according to claims 1 and 2, characterized in that that sodium methylate is used. 4. Process according to claims 1-3, characterized in that the ether used is diisopropyl ether. 5. Process according to claims 1-4, characterized in that a methanolic solution of the condensation product of anhydro-2- (6-acetanilido-1 , 3,5-hexatrienyl) -3, 3-dimethyl-1- (4-sulfobutyl) -4, 5-benzopseudoindolium hydroxide and anhydro-2, 3, 3-trimethyl-1- (4-sulfobutyl) -4, 5-benzopseudoindolium hydroxide mixed with an alkali alcoholate and the resulting indocyanine green by adding of diisopropyl ether precipitates. 6. Iodine-free indocyanine green, produced according to the method of claims 1 - 5.