* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
EXAMPLE 8 4-Amino-6,7-dimethoxy-2-[4-(2-furoyl)piperazine-1-yl]quinazoline hydrochloride Hydrogen chloride gas is bubbled for a period of 8 min. into a cold, stirred mixture of 4-(2-furoyl)piperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine of Example 2 (3.0 g., 7.82 mmoles) in 45 ml. of phosphorus oxychloride. After addition of the hydrogen chloride gas, the reaction mixture is stirred at 25-30 for 10 min. and then heated at 70-75 for a period of 75 min. during which time a gummy solid separates. The reaction mixture is cooled to 30, the excess phosphorus oxychloride removed under reduced pressure and residual material rubbed under ice/water to provide a solid. The solid is collected to afford 2.76 g. (84% yield) of 4-amino-6,7 -dimethoxy-2-[4-(2-furoyl)piperazin-1-yl]quinazoline hydrochloride identical with a sample prepared according to the procedure of U.S. Pat. No. 3,511,836.
EXAMPLE 2 Prazosin Hydrochloride, beta-Form Ten grams of prazosin hydrochloride methanolate, obtained in Example 1 was placed in an oven and held at 110 C., for 24 hours, then cooled to room temperature. The resulting material consisted of monoclinic crystals, M.P. 278-280 C. Analysis: Calc'd. for C19 H21 N5 O4.HCL (percent): C, 54.34; H, 5.28; N, 16.68; Cl, 8.44. Found: C, 54.21; H, 5.26; N, 16.60; Cl, 8.37.
EXAMPLE 4 Prazosin Hydrochloride, alpha-Form The procedure of Example 3 was repeated, except that after evaporating the bulk of the chloroform the isoamyl alcohol slurry was heated at reflux (130-132 C.) for 2 hours. The mixture was then allowed to cool to room temperature, filtered, washed with chloroform and dried in the vacuum oven at 50-60 C. The resulting rod-like crystals melted at 280-282 (dec.). Anal: Calc'd. for C19 H21 N5 O4.HCl (M.W. 419.87): C, 54,35; H, 5.28; N, 16.68; Cl, 8.44 Found: C, 54.38; H, 5.56; N, 16.71; Cl, 8.41.
EXAMPLE 7 Conversion of Prazosin Hydrochloride Methanolate to the alpha-Form A 5 g. sample of the methanolate obtained in Example 1 is refluxed for 3 hours in 100 ml. of 2-methylbutanol. The mixture is allowed to cool to room temperature, washed with dichloromethane, and air dried to afford the alpha-form of prazosin hydrochloride.
7
[ 527-69-5 ]
[ 123-51-3 ]
[ 60547-97-9 ]
[ 19237-84-4 ]
Yield
Reaction Conditions
Operation in experiment
In chloroform; water;
EXAMPLE 3 Prazosin Hydrochloride, gamma-Form 2-(1-Piperazinyl)-4-amino-6,7-dimethoxyquinazoline (57.8 g., 0.20 mole) was dissolved in 1000 ml. of chloroform and 30.2 g. (0.20 mole) of 2-furoyl chloride was added slowly at ambient temperature. When the addition was completed the resulting slurry was stirred for 15 minutes after which 1000 ml. of isoamyl alcohol was added. To the resulting mixture was then added sufficient 10% (w/w) aqueous sodium hyroxide solution to effect the solution of the solid material, about 200 ml. was ordinarily required, while maintaining the mixture at room temperature. The aqueous layer was separated and the organic phase was washed with 250 ml. of water. The organic layer was dried over anhydrous MgSO4, filtered and the filtrate cooled to 0 C. Anhydrous hydrogen chloride was passed through the solution at 0-5 C. until the solution was acidic to moistened test paper (pH about 2-2.5), about 45 minutes was required for the addition. The chloroform was then evaporated at reduced pressure while warming gently to about 45 at 20-30 mm Hg. The vacuum was then released and the solution heated to about 100 C. to remove the last traces of chloroform. The mixture was then allowed to cool to room temperature. The product was recovered by filtration, washed with chloroform and dried in the vacuum oven at 50-60 C. to afford 73.9 g. of needle-like crystals, M.P. 277-279 C. (dec.) of the title polymorph.
Procedures.
When H2O was used as the solvent, 3.0 mL of formaldehyde (40 % v/v) and 1.0 mL of acetylacetone (8.4 % v/v) were mixed in a 10.0 mL tube followed by addition of a drug of the desired concentration. The tube was heated at 100 °C for 25 min. The solution was diluted to 10.0 mL with H2O to obtain the final concentration after cooling to room temperature. Then the fluorescence intensities of the sample and the blank were measured. Relative fluorescence intensity (RFI) is the difference value between the fluorescence intensities of the sample and the blank.