Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-18
2004-04-27
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06727367
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for the resolution of (R,S) 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole into optically enriched and/or optically pure enantiomers and to compounds useful therein.
2-amino-6-(substituted)amino-4,5,6,7-tetrahydrobenzothiazoles having the general formula (A):
wherein R
1
is hydrogen, alkyl or aralkyl group and R
2
is hydrogen, are known pharmaceutical active agents. See for example U.S. Pat. No. 4,843,086 and EP 186087 where these and other tetrahydrobenzthiazole derivatives are taught to be useful in treating schizophrenia, Parkinson's disease or Parkinsonism, and/or hypertension. Among the known compounds is (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole of the formula (B) which is more commonly known as pramipexole.
Pramipexole is commercially sold as a dihydrochloride salt in a peroral formulation.
The compounds of formula (A) have one asymmetric carbon and they may exist either as a single enantiomer or in a mixed or racemic form. The pharmacological activity of compounds of formula (A) is generally connected only or mainly with one isomer thereof. Accordingly, pramipexole is marketed as a single S(−) enantiomer; the dopaminergic activity of the (S) isomer is twice as high as that of the (R) enantiomer.
One general process for preparing compounds of the above formula (A) applicable to a synthesis of pramipexole (general method A) is suggested in U.S. Pat. No. 4,843,086, EP 186087 and EP 207696. The process comprises ring halogenation (preferably bromination) of a substituted aminoketone (C) and the condensation of the so obtained alpha-halogenaminoketone (D) with thiourea to form a 2-aminotetrahydrobenzthiazole ring, as shown in the following scheme:
In practice, compounds of formula (A) comprising a primary amino group or a secondary alkylamino group cannot be prepared from the corresponding compounds of formula (C) directly due to the reactivity of the amino/alkylamino group during preparation, halogenation and cyclization of compounds (C).
The following three variants of the indirect synthetic process leading to pramipexole, i.e. to a compound of formula (A), wherein R
1
is propyl and R
2
is hydrogen, may be derived from the above general method A.
a) Propylation of a compound (A) wherein both R
1
and R
2
is hydrogen.
The starting compound of formula (A), wherein both R
1
and R
2
are hydrogen, may be prepared from a compound (C) 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.
b) Reduction of a carbonyl moiety in a compound of formula (A) wherein R
1
is a propionyl group and R
1
is hydrogen.
A compound of formula (A), wherein R
1
is a propionyl group and R
2
is hydrogen, may be prepared from a compound (C) wherein R
1
is a propionyl group and R
2
is hydrogen.
c) Bromination and cyclization of a compound (C) wherein R
1
is a propyl group and R
2
is a protective group with subsequent removal of the protective group by hydrolysis.
The starting compound (C) may be prepared from a commercially available p-aminocyclohexanol in three steps.
It is apparent that the variant b) is the most straightforward one for production of pramipexole as it does not require introduction and removal of a protective group; instead, the propionyl group serves as a protective group and it is also a direct precursor for the desired propyl group. The corresponding starting compound (C) is however not commercially available and must be prepared in advance.
However, the variants of the above general method A prepare only a racemate. Accordingly, if applied to the synthesis of pramipexole, the above process yields R,S(±)-2-amino-6-propylamino-5,6,7,8-tetrahydrobenzthiazole, which will be further, whenever appropriate, called “racemic pramipexole.”
The above-mentioned patents acknowledge that the produced racemic compound of the general formula (A) may be resolved into single enantiomers by classical methods such as chromatography on a chiral phase or fractional crystallization of a salt with an optically active acid. However, even though the S(−) enantiomer of pramipexole was disclosed and characterised therein, no information is provided how it was prepared; i.e., whether it was prepared by a resolution of racemic pramipexole or from some optically active precursor. Further, no information is provided on how to produce the S(−) enantiomer of pramipexole.
An example of a process for producing optically pure pramipexole was disclosed later by Schneider and Mierau in J.Med.Chem 30, 494 (1987). The authors used the resolution of racemic 2,6-diamino-4,5,6,7-tetrahydrobenzthiazole (compound (A), R
1
═R
2
═H) into enantiomers by fractional crystallization of salts with L(+) tartaric acid. Following the resolution, the corresponding single enantiomer of the resolved diamino-precursor was converted to (−)pramipexole by a two-step propylation comprising a reaction with propionanhydride followed by reduction of the propionyl intermediate.
In conclusion, the known process for preparing optically pure pramipexole by the general method A is the variant a) in the version of Schneider and Mierau. But, this method suffers from several drawbacks including its length and undesirable economics. Thus, there exist a need for a more straightforward production process leading to S(−)pramipexole.
Such a more straightforward process may be the variant b) of the above process; however, it may be commercially interesting only if a feasible process of resolution of the so produced racemic pramipexole into (−)pramipexole is found. As of yet, such a process has not been described.
In ES P200002262, a right of priority therefrom being claimed under 35 U.S.C. §119 in the present application and the entire contents of which are incorporated herein by reference, another process is disclosed for preparing compounds of formula (A) and especially pramipexole, (general method B), said process being outlined in the following scheme.
The process comprises selective monobromination of 1,4-cyclohexandione (D) in an alcoholic solvent to produce a compound of formula (E) wherein 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; a condensation thereof with thiourea to produce a compound of formula (F) wherein R
3
and R
4
are as defined above; and a reaction of the compound (F) with a suitable amine under conditions of reductive amination.
This general method B allows for the production of pramipexole substantially enriched by the desired S(−) enantiomer, e.g. by using a chiral catalyst for the reductive amination to propylamine or using a chiral amine convertible to propylamine as a reagent in the reductive amination. However, it would be further desirable to have a method for directly improving the optical purity of the resulting pramipexole in case the purity is insufficient.
SUMMARY OF THE INVENTION
The present invention relates to the resolution of pramipexole and to the compounds used therein. In particular, one aspect of the invention relates to a monobasic acid addition salt of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole, having the general formula (1)
wherein X is a monovalent anion derived from an acid. Another aspect of the invention relates to a mixed acid addition salt of 2-amino-6-propylamino 4,5,6,7-tetrahydrobenzthiazole, having the general formula (2):
wherein X is a monovalent anion derived from an acid and Y is an anion derived from an optically active acid.
Another aspect of the invention relates to a process that comprises reacting in a solvent a mixture of (R) and (S) monobasic acid addition salts of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole having the formula (1)
wherein
Fleshner & Kim LLP
McKane Joseph K.
Saeed Kamal
Synthon BV
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