Process for the production of 5,6-dihydroxyindolines

Process for the production of 5,6-dihydroxyindolines by ether cleavage of corresponding ether procursors with aqueous hydrogen bromide and subsequent direct crystallization from the aqueous reaction mixture.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a process for the production of 
5,6-dihydroxyindolines by ether cleavage of corresponding ether precursors 
with hydrogen bromide and subsequent direct crystallization from the 
aqueous reaction mixture. 
2. Statement of Related Art 
5,6-Dihydroxyindoline, also known in the literature by the names of 
cyclodopamine and leuconorepinochrome, and 2-carboxy-5,6-dihydroxyindoline 
(synonyms: cyclodopa and leucodopachrome) are of considerable significance 
in the field of medicine and pharmacy and also hair dyes. 
For example, natural hair dyes, so-called melanins, are formed in the 
course of their biosynthesis by oxidative polymerization of 
5,6-dihydroxyindole. Accordingly, numerous attempts have been made in the 
past to use 5,6-dihydroxyindole as a reactive dye precursor in the dyeing 
of hair. Unfortunately, 5,6-dihydroxyindole is extremely unstable in 
aqueous solution both in its free form and in the form of its salts and, 
in the presence of atmospheric oxygen, rapidly forms insoluble, colored 
oxidation and polymerization products which themselves can no longer be 
fixed to the hair. Accordingly, attempts to use 5,6-dihydroxyindole itself 
or salts thereof in dye preparations involve considerable difficulties. 
By contrast, it has been proposed to use 5,6-dihydroxyindolines as a 
pigment precursor in the biomimetic dyeing of hair. In this way, natural 
hair colors can be obtained with melanin dyes via a 5,6-dihydroxyindole 
formed in situ without having to accept any disadvantages due to the known 
stability problems of 5,6-dihydroxyindole. 
The preparation of 5,6-dihydroxyindoline was described for the first time 
by S. N. Mishra and G. A. Swan (J. Chem. Soc. C 1967 1424). The authors 
obtained a solution of 5,6-dihydroxyindoline in hydrochloric acid by ether 
cleavage of 5,6-dimethoxyindoline in an autoclave at 150.degree. C. The 
solution then had to be concentrated by evaporation and the resulting 
crude product purified from ether/ethanol. Unfortunately, this method is 
attended by several disadvantages: (1) the ether cleavage in an autoclave 
involves considerable effort with relatively large batches; (2) to recover 
the crude product, the reaction solution has to be completely concentrated 
by evaporation, so that considerable energy costs are incurred and the 
volume/time yield is reduced, and (3) the recrystallization from readily 
inflammable organic solvents represents a significant risk from the point 
of view of safety in use. 
On the basis of the synthesis of 5,6-dihydroxyindoline by S. N. Mishra and 
G. A. Swan's method, M. Piatelli et al. developed an alternative synthesis 
pathway in which dopamine is first oxidized to norepichrome, the 
norepichrome is reduced to the leuco compound and the leuco compound is 
converted into triacetyl dihydroxyindoline. 5,6-Dihydroxyindoline is 
obtained in crude form from the triacetyl dihydroxyindoline after 
elimination of the acetyl groups. The purification corresponds to that 
described by S. N. Mischra and G. A. Swan. Apart from the complicated 
purification step, this method also has major disadvantages which prevent 
it from being applied on an industrial scale: (1) the oxidation step has 
to be carried out with a heavily diluted solution (approximately 0.5 g 
dopamine per liter) and (2) the intermediate triacetyl dihydroxyquinoline 
has to be purified by column chromatography. 
In complete analogy to this method, the synthesis of 
2-carboxy-5,6-dihydroxyindoline was described by H. Wyler and J. Choivini 
(Helv. Chim. Acta 1961 (51) 1476). They oxidized dopamethyl ester in the 
form of a highly dilute solution to form dopachrome methyl ester and 
reduced the dopachrome methyl ester in situ to form the leucodopachrome 
methyl ester which they then isolated as the triacetyl derivative. The 
triacetyl derivative was then subjected to acidic hydrolysis to form 
2-carboxy-5,6-dihydroxyindoline (leucodopachrome). However, the method is 
attended by the disadvantages described above. Accordingly, the authors 
only obtained a few milligrams of product which was used for spectroscopic 
characterization. 
According to EP-A-462 857, 5,6-dihydroxyindoline can be prepared by 
reaction of 5,6-dimethoxyindoline with aqueous HBr. After the reaction, 
the hydrobromic acid is distilled off, the residue is taken up in ethanol, 
treated with active carbon and filtered through Celite. Ethyl ether is 
then added to crystallize 5,6-dihydroxyindoline. This method is too 
complicated for industrial application. 
DESCRIPTION OF THE INVENTION 
Accordingly, there is a need for an improved process for the production of 
5,6-dihydroxyindolines which, in particular, could even be carried out on 
a relatively large scale. 
It has now surprisingly been found that 5,6-dihydroxyindolines can readily 
be obtained by reacting the corresponding ether precursors with 
hydrobromic acid and directly recrystallizing the 5,6-dihydroxyindolines 
from the aqueous reaction mixture. 
Accordingly, the present invention relates to a process for the production 
of 5,6-dihydroxyindolines corresponding to general formula (I): 
##STR1## 
in which R.sup.1 and R.sup.3 independently of one another represent 
hydrogen or C.sub.1-4 alkyl groups and R.sup.2 is hydrogen, a C.sub.1-4 
alkyl group or a carboxyl group, by reaction of an indoline ether 
corresponding to general formula (II): 
##STR2## 
in which R.sup.1 and R.sup.3 independently of one another represent 
hydrogen or C.sub.1-4 alkyl groups, R.sup.4 and R.sup.5 represent 
C.sub.1-4 alkyl groups or, together with the oxygen atoms to which they 
are attached, form a C.sub.1-4 alkylenedioxy group and R.sup.6 is 
hydrogen, a C.sub.1-4 alkyl group or a group COOR.sup.7 or CONR.sup.7 
R.sup.8 and R.sup.7 and R.sup.8 are hydrogen or a C.sub.1-4 alkyl group, 
with hydrobromic acid, the 5,6-dihydroxyindolines being directly 
crystallized out from the aqueous reaction mixture. 
In one preferred embodiment of the invention, R.sup.3 in formulae (I) and 
(II) is hydrogen. In another preferred embodiment, R.sup.1 in formulae (I) 
and (II) is hydrogen or a methyl group, more particularly hydrogen. 
Indoline ethers (II) in which R.sup.4 and R.sup.5 are C.sub.1-4 alkyl 
groups are normally used in the process according to the invention. In the 
case of methyl groups, methyl bromide is formed therefrom in the course of 
the ether cleavage. Accordingly, it can be of advantage to use indoline 
ethers (II) in which R.sup.4 and R.sup.5 together with the oxygen atoms to 
which they are attached form a C.sub.1-4 alkylenedioxy group, for example 
a methylenedioxy group or an isopropylidenedioxy group. The bromides 
formed during the ether cleavage in this case are less volatile and are 
preferred in the interests of greater safety in use. 
The indoline ethers (II) used may be used either in free form or in the 
form of salts, for example the hydrochloride. 
The process according to the invention may readily be carried out by 
heating the indoline ether (II) in an aqueous solution of hydrogen 
bromide. Basically, there is no particular limit to the concentration of 
the aqueous HBr, although 40 to 62% solutions are preferred. The molar 
ratio of hydrogen bromide to indoline ether (II) is adjusted to a value of 
3:1 to 30:1 and preferably to a value of 5:1 to 15:1. The reaction mixture 
is then heated under reflux for several hours. The reaction mixture is 
worked up simply by cooling, the desired 5,6-dihydroxyindoline (I) 
crystallizing out. After filtration under suction and drying, the 
5,6-dihydroxyindoline is obtained in highly pure form. 
The 5,6-dihydroxyindolines obtained by the process according to the 
invention are suitable as a precursor for oxidation dyes of the type used 
in oxidation colorants for keratin fibers, particularly for human hair.

The following Examples are intended to illustrate the invention without 
limiting it in any way. 
EXAMPLES Example 1 
100 g of 5,6-dimethoxyindoline (0.6 mole) were introduced under nitrogen 
into a stirred vessel and 500 ml of a 62% aqueous hydrogen bromide 
solution (6.6 moles of HBr) were subsequently added. After careful 
heating, the reaction mixture was refluxed for 5 hours. After cooling to 
60.degree. C., the reaction mixture was filtered and 5,6-dihydroxyindoline 
was crystallized out overnight while cooling with ice. The product was 
filtered under suction and dried in vacuo. 
Yield: 100 g of 5,6-dihydroxyindoline hydrobromide (0.46 mole; 78% of the 
theoretical) Melting point: 236.degree.-238.degree. C. (decomposition) 
Purity: 97.8% (according to HPLC) 
Comparison Example 1 
10 g of 5,6-dimethoxyindoline were introduced under nitrogen into a stirred 
vessel and 50 ml of concentrated HCl were added. After careful heating, 
the reaction mixture was refluxed for 5 hours. A thin-layer chromatogram 
of the reaction mixture did not show any 5,6-dimethoxyindoline or 
5,6-dihydroxyindoline zones. 
Comparison Example 2 
10 g of 5,6-dimethoxyindoline were introduced under nitrogen into a stirred 
vessel and 50 ml of a 67% aqueous hydrogen iodide solution were added. 
After careful heating, the reaction mixture was refluxed for 5 hours. A 
thin-layer chromatogram of the reaction mixture did not show any 
5,6-dimethoxyindoline or 5,6-dihydroxyindoline zones. 
The Comparison Examples clearly show that 5,6-dihydroxyindoline can be 
satisfactorily prepared from 5,6-dimethoxyindoline solely with hydrobromic 
acid.