Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-10-27
1999-10-26
Chang, Ceila
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514321, A61K 31445, C07D40512
Patent
active
059731559
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new process for preparing (-)-trans-N-p-fluorobenzoylmethyl-4-(p-fluorophenyl)-3-[[3,4-(methylenedio xy)phenoxy]methyl]-piperidine as well as its pharmaceutically acceptable addition salts.
WO 95/25732 describes the aforesaid compound and its hydrochloride, which is the preferred salt for its therapeutic use. These compounds inhibit 5-hydroxytryptamine reuptake and are surprisingly less toxic than analogous compounds commonly used in therapeutics. Consequently, they are potentially useful in the treatment of depression.
In WO 95/25732 the compound (-)-trans-N-p-fluorobenzoyl-methyl-4-(p-fluorophenyl)-3-[[(3,4-(methylened ioxy)phenoxy]methyl]-piperidine is prepared by reacting (-)-trans-4-(p-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]-piper idine hydrochloride with 2-chloro- or 2-bromo-4'-fluoroacetophenone in an anhydrous alcohol medium, such as that constituted by methanol or ethanol, and in the presence of a mineral base, such as alkali metal carbonates or bicarbonates, that facilitates the uptake reaction of the formed hydracid.
Under these conditions, the reaction product must be separated from the decomposition products by column chromatography, which involves a considerably prolonged operating time as well as a decreased yield that hardly reaches 60%. In addition, the reaction by-products are difficult to remove and their presence has negative repercussions on the samples obtained.
Applicants have surprisingly found out that if instead of starting from (-)-trans-4-(p-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]-piper idine hydrochloride salt the corresponding acetate is used, the solvent ratio can be decreased due to a higher solubility of the acetate in organic solvents. Furthermore, purification of the reaction product by column chromatography is unnecessary, and the resulting product can be directly isolated as a pharmaceutically acceptable addition salt, e.g. as hydrochloride. This provides a significantly higher yield and enhances the purity of the final product. These factors become determinant in the industrial production and constitute the main advantages of the new process disclosed in the present invention.
Thus, the present invention relates to a process for preparing (-)-trans-N-p-fluorobenzoylmethyl-4-(p-fluorophenyl)-3-[[3,4-(methylenedio xy)phenoxy]methyl]-piperidine, as well as pharmaceutically acceptable addition salts thereof, which comprises reacting (-)-trans-(p-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]-piperid ine acetate with 2-chloro (or bromo)-4'-fluoroacetophenone, preferably 2-chloro-4'-fluoroacetophenone, in an alcohol having 1 to 4 carbon atoms and in the presence of a base at an elevated temperature of the mixture, and if desired, converting the resulting compound to a pharmaceutically acceptable addition salt by reaction with the corresponding acid.
Among solvents suitable to carry out the above alkylation reaction, alkanols are preferred. Advantageously employed are those alkanols having one to four carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or 2-methylpropan-1-ol. Especially preferred are methanol and/or ethanol. Mixtures of the above solvents can be employed as well.
Among bases suitable according to the present invention, inorganic bases, in particular mineral bases are preferred. Especially alkali metal carbonates and/or bicarbonates are advantageously used to facilitate uptake reaction of the formed hydracid. Especially preferred are sodium carbonate and/or bicarbonate. Mixtures of bases can be employed as well.
It is advisable to perform the reaction at an elevated temperature, preferably at the boiling temperature of the mixture.
According to the present invention the resulting (-)-trans-N-p-fluorobenzoylmethyl-4-(p-fluorophenyl)-3-[[3,4-(methylenedio xy)phenoxy]methyl]-piperidine, i.e. the free base form, can be converted to a pharmaceutically acceptable addition salt. Advantageously, the acid corresponding to the desired addition salt is reacted with sai
REFERENCES:
patent: 5665736 (1997-09-01), Foguit et al.
Berge et al. "Pharmaceutical salts" J. PHarm. Sci. V. 66, pp. 1-2, 1977.
Foguet Rafael
Gubert Santiago
Ortiz José A.
Sacristan Aurelio
Chang Ceila
Ferrer Internacional S.A.
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