Process for preparing a scopine ester intermediate

Details Process for preparing a scopine ester intermediate Process for preparing a scopine ester intermediate

2002-08-19

2003-01-14

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S125000

Reexamination Certificate

active

06506900

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a new process for preparing a scopine ester useful as an intermediate in preparing (1&agr;,2&bgr;,4&bgr;,5&agr;,7&bgr;)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0
2,4
]nonane-bromide.
BACKGROUND OF THE INVENTION
The compound (1&agr;,2&bgr;,4&bgr;,5&agr;,7&bgr;)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0
2,4
]nonane-bromide is known from European Patent Application EP 418 716 A1 and has the following chemical structure:
The compound has valuable pharmacological properties and is known by the name tiotropium bromide (BA679). Tiotropium bromide is a highly effective antichoinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).
Tiotropium bromide is preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) may be used, which are administered using corresponding powder inhalers. Alternatively, it may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas.
In view of its great efficacy, tiotropium bromide can be used in low therapeutic doses. On the one hand this imposes particular demands on the pharmaceutical production of the formulation to be used, and on the other hand it is particularly necessary to develop an industrial process for synthesising tiotropium bromide which ensures that the product is prepared not only in a good yield but also with exceptional purity.
European Patent Application EP 418 716 A1 discloses a method of synthesising tiotropium bromide. It corresponds to the method diagrammatically shown in Diagram 1.
Diagram 1
In a first step, scopine (II) is reacted with methyl di-(2-thienyl)-glycolate-(III) to form di-(2-thienyl)-glycolic acid scopine ester (IV), which is then quaternized to form tiotropium bromide.


REFERENCES:
patent: 5610163 (1997-03-01), Banholzer et al.
patent: 5770738 (1998-06-01), Banholzer et al.
patent: 0 418 716 (1991-03-01), None
Petrovic, G. et al; “Synthesis of Acetyl Scopine. Intramolecular Reactions of N-Carbethoxy Nortropine-3alpha-benzenesulfenate”; Synlett 1999, No. 5, 635-637.

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