Flavoxate Hydrochloride

Yuri Goldberg    Apotex Inc. 150 Signet Drive Toronto, Ontario M9L 1T9 Canada

1 Description

1.1 Nomenclature

1.1.1 Systematic Chemical Names

2-(1-Piperidino)ethyl 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate hydrochloride

2-(1-Piperidino)ethyl 3-methylflavone-8-carboxylate hydrochloride

2-(1-Piperidino)ethyl ester of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, hydrochloride

1-Piperidineethanol, 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate, hydrochloride

1.1.2 Nonproprietary Names

Flavoxate Hydrochloride

1.1.3 Proprietary Names [1,2]

Urispas, Bladderon, Genurin, Spasuret, Patricin

1.2 Formulae

1.2.1 Empirical Formula, Molecular Weight, CAS Number

1.2.1.1 Free base

C24H25NO4 [MW = 391.47]

CAS number = 15301-69-6

1.2.1.2 Hydrochloride salt

C24H25NO4•HCl [MW = 427.96]

CAS number = 3717-88-2

1.2.2 Structural Formula

1.3 Elemental Analysis

The calculated elemental composition, and that obtained in this work, is as follows:

1.4 Appearance

Flavoxate hydrochloride is a white or almost white crystalline powder [3].

1.5 Uses and Applications

Flavoxate hydrochloride is a synthetic urinary tract antispasmodic that exerts a direct spasmolytic effect on smooth muscle and provides therapeutic benefits in a variety of urological disorders. Flavoxate is applied in the symptomatic treatment of dysuria, urgency, nocturia, supraburic pain, frequency, and urge incontinence due to a variety of urological conditions [4-12].

2 Method(s) of Preparation [13]

The synthetic route for the preparation of Flavoxate HCl is shown in Scheme 1. The key intermediate, 3-methyl-2-phenylflavone-8-carboxylic acid (7), was obtained starting from 2-hydroxy-3-nitropropiophenone (1). Methylation of (1) with dimethyl sulfate, followed by reduction of intermediate (2) with iron in hydrochloric acid, furnished 3-amino-2-methoxypropiophenone (3). The latter was converted into the corresponding cyano derivative (4) by means of the Sandmeyer reaction. Cleavage of the methoxy group of (4) yielded the phenolic intermediate (5) suitable for the cyclization to the substituted flavone (6) by reaction with benzoyl chloride/sodium benzoate at elevated temperature (180-190 °C). Acidic hydrolysis of (6) gave rise to the desirable derivative of flavone-8-carboxylic acid (7).

The latter method was employed to prepare a number of basic esters by reacting the corresponding acid chloride with a number of 2-(alkylamino)ethanols. When 2-(1-piperidino)ethanol was used, the reaction gave 2-(1-piperidino)ethyl 3-methyl-4-oxo-2-phenyl-4H-1- benzopyran-8-carboxylate hydrochloride (i.e., Flavoxate HCl). Alternatively, the intermediate cyano substututed flavone (4) can be obtained from 3-methyl-8-aminoflavone (readily obtainable from (1) [14]) by applying the Sandmeyer reaction [13].

3 Physical Properties

3.1 Ionization Constants

Flavoxate free base is characterized by a single ionization constant, for which the pKa was determined by potentiometric titration to be 7.3 (in water at 37 °C) [15].

3.2 Solubility Characteristics

The solubilities of Flavoxate hydrochloride in different solvents are summarized in Table 1, and the pH dependence of the aqueous solubility is found in Table 2. Flavoxate free base is practically insoluble in water (0.001% w/v at 25 °C), but soluble in common organic solvents (chloroform, methanol, ethanol, acetone and ethyl ether) [15,16].

3.3 Partition Coefficients

The octanol / water partition coefficient of Flavoxate hydrochloride was found to be 2.01. The distribution coefficient between octanol and 0.1 N HCl was found to be 4.51, and the distribution coefficient between octanol and pH 7.4 phosphate buffer was determined as 84.0 [15].

3.4 X-Ray Powder Diffraction Pattern

The x-ray powder diffraction pattern of Flavoxate hydrochloride was obtained on a Philips PW3710 diffractometer using Cu Kα radiation, and is shown in Figure 1. The sample exhibited a number of scattering peaks indicative of well-formed molecular planes in the crystals. A summary of the scattering angles, d-spacings, and relative intensities is provided in Table 3 (only peaks having relative intensities greater than or equal to 1% are listed).

3.5 Thermal Methods of analysis

3.5.1 Melting Behavior

In separate reports, Flavoxate hydrochloride has been found to melt with decomposition at 232-234 °C [13], and at 230-233 °C [15] (uncorrected). The melting point range obtained in the present work was 235.2-238.6 °C (corrected).

3.5.2...