Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-08-07
2004-08-03
Solola, Taofiq (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06770761
ABSTRACT:
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.
BACKGROUND AND PRIOR ART
The 2-(acyl)amino-6-(substituted)amino-4,5,6,7-tetrahydrobenzothiazoles having the general formula (1):
wherein R is hydrogen or acyl group, R
1
is hydrogen, alkyl or aralkyl group and R
2
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(−)-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 R
1
, R
2
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 R
1
and R
2
are hydrogen, is prepared from a compound (3) wherein either R
1
is an amino-protective group such as an acyl or alkoxycarbonyl group and R
2
is hydrogen or R
1
-R
2
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 R
1
is acyl and R
2
is hydrogen, is prepared from a compound (3) wherein R
1
is acyl and R
2
is hydrogen.
A compound of formula (1), wherein R
1
is alkyl or aralkyl and R
2
is hydrogen, is either prepared from a compound (3) wherein R
1
is alkyl or aralkyl and R
2
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 R
1
and R
2
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 R
1
is acyl or arylacyl and R
2
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), R
1
=R
2
=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), R
1
═H, R
2
═CO—CH
3
and/or R
1
, R
2
=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(−) 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), R═R
1
═R
2
═H) 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.
DESCRIPTION OF THE INVENTION
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, R
1
is hydrogen, lower alkyl or aralkyl group and R
2
is hydrogen,
comprising a reaction of a compound of formula (6),
wherein R is hydrogen or acyl group, R
3
and R
4
are either the same and each of them represents an alkoxy group of 1-4 carbons or they together form a C
2
-C
5
alkylenedioxy group or an oxo-group,
with an amine of general formula (7)
R
1
—NH
2
(7)
wherein R
1
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 R
3
and R
4
are as defined above are novel and they represent a second aspect of the present invention. As th
Hoorn Hans Jan
Lemmens Jacobus Maria
Peters Theodorus Hendricus Antonius
Pospisilik Karel
Buscher Mark R.
Solola Taofiq
Synthon BV
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