The present invention relates to a novel process for preparing 2-amino-6-alkylamino-4,5,6,7-tetrahydrobenzothiazoles and to certain intermediates useful therein.
The 2-(acyl)amino-6-(substituted)amino-4,5,6,7-tetrahydrobenzothiazoles having the general formula (1): 
wherein R is hydrogen or acyl group, R1 is hydrogen, alkyl or aralkyl group and R2 is hydrogen,
are useful pharmaceutical agents. Some of these compounds are known to have dopamine D-2 agonist activity. The compounds of formula (1) include S(xe2x88x92)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (pramipexole) of the formula (2) 
which is a commercial product used for treatment of Parkinson""s disease and schizophrenia and is marketed, in a form of a dihydrochloride, under several brand names e.g. Mirapexin[TM].
The compounds of formula (1) are described in EP 186087.
Several methods for preparing compounds of the above formula (1) are suggested in EP 186087 and EP 207696. A common core of these methods is a process comprising ring halogenation preferably bromination) of a substituted aminoketone (3) and the condensation of the so obtained alpha-halogenaminoketone (4) with thiourea or N-acylthiourea to form a 2-aminotetrahydrobenzothiazole ring, as shown in the following scheme: 
Dependent on the nature of substituents R1, R2 in (3) and (4) and on the desired structure of the product (1), the corresponding amino substituents which are desired to be in position 6 of compounds (1) may or have to be accordingly modified before and after this two-step condensation.
A compound of formula (1), wherein both R1 and R2 are hydrogen, is prepared from a compound (3) wherein either R1 is an amino-protective group such as an acyl or alkoxycarbonyl group and R2 is hydrogen or R1-R2 together form an imino-protective group such as phthalimidogroup. After halogenation and condensation with thiourea, the protective group is removed in a separate step.
A compound of formula (1), wherein R1 is acyl and R2 is hydrogen, is prepared from a compound (3) wherein R1 is acyl and R2 is hydrogen.
A compound of formula (1), wherein R1 is alkyl or aralkyl and R2 is hydrogen, is either prepared from a compound (3) wherein R1 is alkyl or aralkyl and R2 is hydrogen or a protective group (with subsequent deprotection in that later case), or it can be prepared by alkylation/aralkylation of the compound (1) wherein both R1 and R2 is hydrogen or, finally, it can be prepared by metal hydride or borane reduction of the acyl group in a compound of formula (1) wherein R1 is acyl or arylacyl and R2 is hydrogen.
In all the above cases, the acyl substituent R should be furthermore hydrolysed to hydrogen, whenever necessary.
If desired, the produced compounds of formula (1) may be converted into salts with inorganic and organic acids, particularly with acids which are pharmaceutically acceptable.
Thus, in total, the overall synthetic process represents a sequence of at least four synthetic steps. In practice, a primary aminogroup or a secondary alkylaminogroup present in the compounds of formula (1) cannot be introduced and maintained during oxidation, bromination and cyclization step without introduction a protective group, due to its reactivity. The protective group must be removed afterwards.
In the case of pramipexole and similar compounds, the following synthetic sequence from the cited prior art is suggested to be most useful.
The last step of the overall synthesis comprises reductive alkylation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (compound (1), R1=R2=H), e.g. by propionaldehyde/sodium borohydride; the starting diamino-compound has been prepared by a sequence starting from 4-aminocyclohexanol which has been acetylated or phthalidated and subsequently oxidised to yield acetamido- or 4-phthalirnidocyclohexanone which has been monobrominated and subsequently reacted with thiourea to give 6-acetamido (or 6-phthalimido)-2-amino-4,5,6,7-tetrahydrobenzothiazole (compound (1), R1xe2x95x90H, R2xe2x95x90COxe2x80x94CH3 and/or R1, R2=phtalimido); finally, the protective acetyl or phthalimido group has been removed.
Thus, in practice, the overall synthetic sequence, starting from commonly available material, represents six synthetic steps.
In addition, the compounds of formula (1) have an asymmetric carbon and they exist either as single enantiomers and/or in a racemic form. The pharmacological activity of compounds of formula (1) is however generally connected only or mainly with one stereoisomer thereof; for instance, pramipexole is marketed as a single S(xe2x88x92) isomer and the dopaminergic activity of the said isomer is twice as high as that of the R(+) isomer. The cited prior art process allows preparing only a racemate. It is anticipated that, if the product of formula (1) has a chiral atom, the produced racemic compound may be resolved into optical isomers by classical methods such as chromatography or fractional crystallisation. Generally it should thus be expected that, in industrial scale, the produced racemic compounds of formula (1) are resolved into optical isomers by adding a next production sequence comprising steps of forming a salt with an appropriate optically active acid, resolution of salts by fractional crystallisation and, if necessary, liberating the free base of the resolved product from the salt. An example of such resolution process in the case of producing optically pure pramipexole has been disclosed by Schneider and Mierau in J. Med. Chem 30, 494 (1987), using the diaminoderivative (compound (1), Rxe2x95x90R1xe2x95x90R2xe2x95x90H) as a substrate and L(+) tartaric acid as a resolution agent. Following to the resolution, optically active pramipexole has been prepared by two-step propylation of the single enantiomer of the diamino-precursor comprising reaction with propionanhydride followed by reduction of the propionyl intermediate.
It is apparent that the prior art processes for preparing compounds of formula (1) suffers from severe drawbacks, as they are lengthy and economically undesirable. Thus, there exist a need for a more straightforward production process.
As the result of the present inventors"" continuous study to establish a more economical and simple process for producing compounds of formula (1), a novel, straightforward and efficient process has been found enabling synthesis of compounds (1) in two steps from easily available 1,4-cyclohexanedione, by employing novel intermediates and a novel way of conversion of such new intermediates to compounds (1). Particularly, the process of our invention raises a potential to prepare the compound (1) enriched by a single enantiomer thereof.
According to the first aspect of the present invention, there is provided a process for preparing compounds of formula (1) 
wherein R is hydrogen or acyl group, R1 is hydrogen, lower alkyl or aralkyl group and R2 is hydrogen,
comprising a reaction of a compound of formula (6), 
wherein R is hydrogen or acyl group, R3 and R4 are either the same and each of them represents an alkoxy group of 1-4 carbons or they together form a C2-C5 alkylenedioxy group or an oxo-group,
with an amine of general formula (7)
R1xe2x80x94NH2xe2x80x83xe2x80x83(7) 
wherein R1 is as hereinbefore defined,
in a presence of a reducing agent or a hydrogen gas with hydrogenation catalyst, optionally followed, if a compound (1) with R=acyl is produced, by hydrolysis of the acyl group to hydrogen, and isolation of the resulted compound of formula (1) as a free base or as an acid addition salt, incl. any hydrate or solvate thereof.
In a particular aspect, there is provided a process as defined above wherein the compound of formula (1) is produced substantially enriched by a single enantiomer, by using stereospecifically reducing agent or a chiral hydrogenation catalyst.
The compounds of formula (6) wherein R3 and R4 are as defined above are novel and they represent a second aspect of the present invention. As the preferred compounds, 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole (compound (6), Rxe2x95x90H, R3, R4 is xe2x95x90O group), 2-amino-6,6-dimethoxy-4,5,6,7-tetrahydrobenzothiazole (compound (6), Rxe2x95x90H, R3 and R4 are methoxy groups), 2-acetamido-6-oxo-4,5,6,7-tetrahydrobenzothiazole (compound (6), R=acetyl, R3, R4 is xe2x95x90O group) and 2-acetamido-6,6-dimethoxy-4,5,6,7-tetrahydrobenzothiazole (compound (6), R=acetyl, R3 and R4 are methoxy groups) are claimed, as well as acid addition salts thereof.
In a third aspect, the present invention provides a process for producing a compound of formula (6) wherein R3 and R4 are as defined above, said process comprising bromination of 1,4-cyclohexandione (5) in an alcoholic solvent to yield a compound of formula (8) 
wherein R3 and R4 are as defined above,
followed by reaction with thiourea or N-acylthiourea. In a preferred aspect, the reaction is performed without isolation of intermediate product of the general formula (8). If desired, the acyl group R may be subsequently hydrolysed to hydrogen.
The overall process of the present invention is illustrated by the following reaction scheme: 
As shown by the above reaction scheme, the first step of a process of the present invention is characterised by a novel finding that 1,4-cyclohexanedione (5) can be selectively monobrominated to give an intermediate (8). Though seeming to be a simple compound, no records of successful monobromination of 1,4-cyclohexanedione (5) have been found in any prior art disclosure and the intermediate (8) has not been described and/or characterised so far.
We have found out that the monobromination of 1,4-cyclohexandione (5) cannot be achieved if attempting to brominate the substrate under xe2x80x9cclassicalxe2x80x9d conditions, e.g. by using bromine in acetic acid or in a halogenated hydrocarbon (e.g. in chloroform) and at slightly elevated temperatures, which conditions could be regarded by a skilled chemist as quite suitable for the reaction as the substrate is well soluble in these solvents. Indeed, bromine apparently reacts with the substrate, but the reaction product is different: immediate elimination of hydrogen bromide and formation of hydroquinone system follow the bromination.
After thorough experimental work resulting into our invention, we were successful in finding conditions, under which the desired compound (8) could be formed reliably. It was found that a substantial condition for successful monobromination of (5) is to perform the bromination reaction in an alcohol as a reaction medium. A relatively stable product of bromination can be obtained only under a condition if the keto-groups are masked as a ketal; the alcohol is thus also a reaction partner for such ketalization. As the alcohol, a lower alkanol of one to four carbon atoms (e.g. methanol, ethanol, n-propanol) or an alkyleneglycol of two to five carbon atoms (e.g. ethylene glycol or 2,2,-dimetylpropyleneglycol) may be employed, though other alcohols are not specifically excluded. Methanol is the most preferred alcohol for the bromination.
The proper substrate for the bromination is thus in fact a compound of formula (9) 
wherein R3 and R4 either represent the same alkoxy group or they together form an alkylenedioxy group. The term xe2x80x9calkoxyxe2x80x9d represents a straight or branched alkoxy group having one to four carbon atoms; the term xe2x80x9calkylenedioxyxe2x80x9d represents a group wherein the alkylene moiety consists from two to five carbon atoms.
The product of the bromination of the formula (8) is indeed still a quite unstable compound. Thus, the bromination reaction should advantageously be followed by the reaction with thiourea without isolation of the compound (8); however, the step of isolation of the intermediate (8) is not specifically excluded from this invention. The second advantage of the alcoholic solvent is that it can serve as a reaction medium also for the reaction with thiourea. The primary product (6) is the ketal (i.e. R3, R4 are alkoxy groups or alkylenedioxy group); however, the ketal can be easily converted into a 6-oxo compound in the presence of water. Water can be either added intentionally, both after the reaction with thiourea (to the reaction mixture or to isolated ketal) and before the reaction of thiourea, or it may be present in the reaction mixture as a product of reaction from preceded steps. The deketalisation to 6-oxo compound generally requires the presence of an acid; herein, the hydrogen bromide liberated from the reaction with thiourea can serve as the acid catalyst.
It is not decisive whether the product (6) is isolated after the reaction with thiourea in a form of a ketal or as a 6-oxo compound or as a mixture of these two compounds. Both types of the substrate are equally suitable for the subsequent amination. The product (6) may be isolated as a free base or as an acid addition salt; preferred salt is a hydrobromide.
In the last (i.e. the second) production step, the isolated product (6) or the mixture of products (6) is subjected to the reductive amination with ammonia or corresponding alkylamine (7) in presence of a reducing agent to give requested compound of the formula (1). The reaction is advantageously carried out in a suitable solvent or in a mixture of solvents such as methanol, ethanol, tetrahydrofuran, dimethylformamide, conveniently at temperatures of between 0-50xc2x0 C., preferably at temperatures of between 0-30xc2x0 C. Sodium cyanoborohydride is the reducing agent of choice as it selectively reduces imines while it doesnot reduce oxo-group (so that the yet unreacted starting (6) is basically not reduced to an alcohol in a side reaction), although other conventional metal hydrides as sodium borohydride or diisobutylaluminium hydride can also be employed. Alternatively, the reaction may be performed under conditions of catalytic hydrogenation; however, care is to be taken in selection of hydrogenation catalysts as the sulphur present in the molecule of the substrate can poison the catalyst. Useful hydrogenation catalyst is e.g. palladium/carbon catalyst.
When using an alkylamine for reductive amination, an imine of the formula (10) 
wherein R and R1 are the same as above, is formed as an intermediate. Such compound may be isolated in case of need and can be subjected to a reduction to (1) in a separate step.
If using conventional reduction or hydrogenation agents, the desired compound (1) is formed as a racemate; however, in a specific feature of the invention, there may be employed also agents allowing enantioselective reductive amination, thus yielding a compound of formula (1) which is enriched by the desired enantiomer. Such agents are known in the art, e.g. as described in U.S. Pat. No. 5,292,893 or WO 97/11934.
The reductive amination of a compound (6), particularly an enantioselective reductive amination, may be also performed indirectly. This alternative is useful for preparation of compounds of formula (1) wherein the substituent R1 is an alkyl group of at least three carbon atoms. The reaction partner of the compound of the formula (6) is now a precursor of the amine (7)xe2x80x94a chiral amine of the formula (7a) 
bearing a hydrogen-replaceable substituent X on the centre of chirality. Such an amine reacts with the compound (6)xe2x80x94under conditions substantially identical with those as described above- to yield a compound of the formula (11). 
The presence of a centre of chirality in (7a) aids to direct the reductive amination asymetrically so that the compound (11) may be preparable as enriched by one enantiomer.
In a subsequent step, the substituent X should be replaced by hydrogen to form the compound of formula (1), substantially without racemization on the tetrahydrobenzthiazole ring. Any substituent replaceable by hydrogen but resistant to the conditions of reductive amination may be chosen; advantageously, the starting chiral amine (7a) may be an amine wherein X is a hydroxy group or a halogen atom.
It is apparent that the substituent R5 in the compounds (7a) and (11) is a precursor for the R1 substituent and should be an alkyl group of two carbon less than the desired group R1. Furthermore it is apparent that R5 and X must not be identical to maintain the chiral centre.
The compounds of general formula (11), the process of their formation and that of their transformation to compounds (1) are novel and form another aspect of the present invention.
Another alternative of reductive amination is based on the reaction of a compound of formula (6) with N-alkylhydroxylamine. In this case, an iminoxide is formed as the intermediate and it may be reduced similarly as the imine. Reduction of the iminoxide may also produce a compound enriched by one enantiomer.
The enrichment, in optimum case, could be close to 100%. If not, the amount of undesired enantiomer in the product may be further diminished by means of conventional optical resolution, e.g. by fractional crystallisation of salts with an optically active acid or by chromatography on a chiral phase.
Before or after the reductive amination, the acyl group R may be hydrolysed to hydrogen, if desired. Such hydrolysis can be performed by conventional methods, preferably by alkaline hydrolysis.
If the product of the reductive amination (with or without a subsequent resolution into optical enantiomers) is a compound wherein R1 is hydrogen, it may be converted into another compound of formula (1) wherein R1 is an alkyl group or an aralkyl group, by conventional methods of alkylation or aralkylation of primary amines.
The compounds of formula (1) may be isolated from reaction mixture as free bases or they may be converted into acid addition salts and isolated in solid state by methods known per se. Preferred acids useful to form addition salts are pharmaceutically acceptable acids such as, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, oxalic, maleic, fumaric, tartaric, malic, benzoic, methanesulfonic, benzenesulphonic or p-toluenesulfonic acid. The compounds or salts thereof may be also isolated in solvated or hydrated form.
Specifically, the process of our invention and the novel intermediates resulted therefrom are advantageous in the preparation of pramipexole. In the most preferred arrangement for production of praripexole, the bromination reaction of 1,4-cyclohexandione is carried out in methanol under temperatures close to ambient, and the reaction with thiourea with the product of brormination is performed without isolation thereof, i.e. in the same reaction vessel. The product of the condensation, either the ketal or the ketone, is insoluble in the reaction medium and can be easily isolated by conventional methods of filtration or centrifugation, as a hydrobromide or as a free base. If necessary, this intermediate product may be further purified by conventional methods, e.g. by crystallisation.
In the following step, the above intermediate reacts with propylamine and/or with a salt of propylamine, in a presence of a reducing agent such as sodium cyanoborohydride, in temperatures close to ambient and in an inert organic solvent. The intermediating imine is not isolated. After removal of inorganic salts and the excess of propylamine, the desired product can be isolated as a salt with an inorganic or organic acid, e.g. with hydrochloric acid, by crystallisation from a suitable solvent, e.g. from ethanol.
Alternately, undirect reductive amination with a chiral amine as described above may be employed for the pramipexole synthesis. The advantageous chiral amine for this reaction is S(xe2x88x92) 2-hydroxypropylamine. The intermediating product is 2xe2x80x2-hydroxypramipexole (compound (11), R5xe2x95x90CH3, Xxe2x95x90OH) and, in the subsequent step, the OHxe2x80x94 group on the side chain thereof is removed by a suitable dehydroxylation agent or method, e.g via a iodo-compound (compound (11), R5xe2x95x90CH3, Xxe2x95x90J).
If the produced pramipexole is a racemate or it is not sufficiently enriched by the desired S(xe2x88x92) enantiomer, there may be employed a step of optical resolution, i.e. the removal of the undesired R(+) enantiomer by a fractional crystallisation of salts of both enantiomers of pramipexole with an optically active acid. Advantageously, L(+) tartaric acid is suitable for use in such resolution step.
The present invention is more particularly described and explained by the following examples. It is to be understood, however, that the present invention is not limited to these examples and various changes and modifications may be made without departing from the scope of the present invention.
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