Process for preparing an anticholinergic

Details Process for preparing an anticholinergic Process for preparing an anticholinergic

2001-12-19

2002-11-26

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

06486321

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a new process for 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 anticholinergic 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.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that, surprisingly, tiotropium bromide can be obtained in much purer form if it is synthesised by a different method from that described in EP 418 716 A1. This alternative and surprisingly more advantageous method is diagrammatically illustrated in Diagram 2.
Diagram 2
Starting from the tropenol (V) known in the art and reacting with di-(2-thienyl)-glycolic acid derivatives (VI), first the tropenol di-(2-thienyl)-glycolate (VII) is formed. This is converted into the corresponding scopine ester (IV) by epoxidation of the olefinic double bond.
Accordingly, the present invention relates to a process for preparing tiotropium bromide (I)
characterised in that the tropenol ester of formula (VII)
is oxidised to form the scopine ester of formula (IV)
which is then quaternized with methyl bromide to form tiotropium bromide (I).
Because of the central importance of the tropenol ester of formula (VII) according to the invention, in another aspect, the present invention relates generally to the use of the tropenol ester (VII), optionally in the form of the acid addition salts thereof, for preparing tiotropium bromide (I). In another aspect, the present invention relates to the use of the tropenol ester (VII), optionally in the form of the acid addition salts thereof, for preparing the scopine ester of formula (IV).
When tropenol ester (VII) is used in the form of an acid addition salt for preparing the scopine ester (IV), this acid addition salt is preferably selected from among hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate; the hydrochloride and hydrobromide are particularly preferred.
According to another aspect, the present invention relates to a process for preparing tiotropium bromide of formula (I)
characterised in that in a first step tropenol of formula (V),
optionally in the form of the acid addition salts thereof, is reacted with an ester of formula (VI)
wherein R denotes a group selected from among hydroxy, methoxy, ethoxy, O—N-succinimide, O—N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, —S-methyl, —S-ethyl and —S-phenyl, to form the tropenol ester of formula (VII)
which is then epoxidised in a second step to form the scopine ester of formula (IV)
and this is then quaternized in a third step using methylbromide to obtain tiotropium bromide (I).
Because of the central importance of the tropenol (V) as a starting material for preparing tiotropium bromide (I), in another aspect the present invention further relates to the use of tropenol (V), optionally in the form of the acid addition salts thereof, as a starting material for preparing tiotropium bromide (I).
To prepare the tropenol ester (VII), tropenol, optionally in the form of an acid addition salt thereof selected from among the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate, preferably in the form of the hydrochloride or hydrobromide, most preferably in the form of the hydrochloride, is taken up in a suitable organic solvent, preferably in a solvent selected from among toluene, benzene, n-butylacetate, dichloromethane, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidinone, preferably selected from among toluene, benzene, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidinone, most preferably toluene or benzene, toluene being most particularly preferred as the solvent. According to the invention, 0.5-3 l, preferably 0.75-2.5 l, most preferably between 1.25 and 1.75 l of organic solvent are used per mol of tropenol (V) put in.
If tropenol is used in the form of an acid addition salt thereof, a base is added to the resulting mixture to liberate the tropenol. Suitable bases according to the invention are inorganic or organic bases, organic amines being particularly preferred. Organic amines which may be used include triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, N-methylpyrrolidine, N-methylmorpholine or ammonia, the use of triethylamine, diisopropylethylamine, pyridine or ammonia being particularly preferred, while ammonia is most particularly preferred. At least 1 mol, preferably 1.25 to 2.5 mol, most preferably 1.5 to 2 mol of amine are added, per mol of tropenol salt used. The amine may be added at temperatures of between 0 and 60° C., preferably 15 to 50° C., most preferably 20 to 30° C. After the amine has been added, the suspension obtained is stirred at constant temperature for between 0.1 to 5 h, preferably between 0.5 to 2.5 h, most preferably between 0.75 and 1.5 h.
The ammonium salt thus obtained is filtered off and optionally washed with the organic solvent mentioned above. Between 0.1 and 1.5 l, preferably 0.3-1.0 l of solvent are used per mol of tropenol (V) put in.
Some of the solvent is distilled off in vacuo at elevated temperature, preferably at 30-80° C., most preferably at 40 to 60° C. The distillation temperature naturally depends on the choice of solvent used. Depending on the choice of solvent, the vacuum is adjusted so that distillation takes place in the temperature range specified above. Between 0.25 and 2 l, preferably 0.5-1.5 l of solvent are distilled off per mol of tropenol (V) put in. After the specified amount of solvent has been distilled off, the reaction solution is cooled to a temperature range of from 0-50° C., preferably to 15-35° C., and the di-(2-thienyl)glycolic acid derivative (VI) is added. Di-(2-thienyl)glycolic acid derivatives (VI) which may be used according to the invention are those compounds wherein R denotes hydroxy, methoxy, ethoxy, O—N-succinimide, O—N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, —S-methyl, —S-ethyl or —S-phenyl. It is particularly preferred to use the compound (VI) wherein R denotes hydroxy, methoxy or ethoxy, most preferably methoxy or hydroxy. If the compound wherein R is hydroxy is used as the compound (VI), the reaction may be carried out in the prese

Affiliated with

Also associated with

Rating

Process for preparing an anticholinergic does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for preparing an anticholinergic, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing an anticholinergic will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2954991