CS266560B2 - Metho of sorbinile preparation - Google Patents

Description

S-6-fluorspirol-Croman-4,4'-imidazolidine-2 ', 5'-dione, also called S-2,3-dihydro-6-fluorspiro-4H-1-benzopyran-4,4'-imidazolidine -2 ', 5'-dione (USAN: sorbinil) of formula I

YEAH Hl К ÍJ ^(I) is a highly potent inhibitor of aldos reductase, which is particularly important in effective control

chronic complications of diabetes mellitus (Sarges US Patent No. 4,130,714). The present invention relates to an improved process for preparing sorbinil and intermediates used in the improved process.

To date, sorbinil has been prepared by resolution of racemic 2,3-dihydro-6-fluorospiroC4H-1-benzopyran-4,4'-imidazolidine-2 ', 5'-dione using highly toxic brucine as a resolving agent in a large volume of solvent (US Patent 4 130,714).

Surprisingly, it has now been found that resolution of the racemate can be carried out directly through the (-) - 3-aminomethylpinan salt of sorbinil. Good yields of sorbinil are obtained with far lower volumes of solvent, while at the same time the use of a highly toxic resolving agent has been eliminated. The efficiency of the process was further enhanced by isolating the undesired enantiomer from the mother liquors and recycling the fresh racemate via the 6-fluoro-6-chromanone precursor.

Sorbinil has also recently been prepared by an alternative synthesis in which the desired chirality is introduced during a synthetic sequence (Sarges US Patent No. 4,286,098).

The present invention provides a process for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof, which comprises:

and) (-) - 3-aminomethylpinan crystallizes sorbinil salt from a solution of racemic hydantoin of formula II CL | IH Fx HnJ ΥΊιΐ 1 ⁰ (II) and uv (b) this aminopinate salt is converted to sorbinil or a pharmaceutically acceptable salt thereof.

The present invention further encompasses as obtained intermediates a chiral salt of sorbinil with amines, wherein said chiral amine is selected from the group consisting of (-) - 3-aminomethylpinane, (+) - 3-aminomethylpinane, (-) - 2-amino-2-norpinane and quinine. Of particular interest are those amine salts which are crystallizable in crystalline form, such as the (-) - 3-aminomethylpinan salt and the sorbinil quinine salt.

The process according to the invention is easy to carry out. To prepare sorbinil by direct resolution, the racemate is suspended or dissolved in a solvent, preferably a lower alkanol or a mixture of lower alkanols, by heating to 50 to 90 ° C. A preferred solvent is a mixture of methanol and isopropanol in a ratio of about 0.1 by volume, preferably heated to boiling (about 69-71 ° C). Substantially one molar equivalent of (-) - 3-aminomethylpinane, preferably dissolved in a portion of the solvent, is added to the hot suspension or solution to obtain a solution.

CS 266 560 B2 diastereomeric salts. The ammonium salt is slowly cooled to about 0-5 ° C and the resulting crystalline solids are granulated in a conventional manner for some time prior to isolation. Such slow cooling and granulation minimizes occlusion of undesired diastereomeric salts. The volume of the solvent is selected so as to obtain the sorbinil salt in as large a quantity as possible while minimizing the amount of this undesired enantiomeric salt, then it is easily removed by optional recrystallization from the same alkanol or alkanol mixture. The (-) - 3-aminomethylpinpin salt of sorbinil is then converted to sorbinil or a pharmaceutically acceptable salt thereof by standard methods known in the art. For example, the ammonium salt is partitioned between at least one equivalent of aqueous acid and a water-immiscible organic solvent, the sorbinil is separated by concentrating the organic phase and / or adding a substance in which the sorbinil does not dissolve. If a pharmaceutically acceptable salt with a cation is desired, the sorbinil is extracted back into water containing substantially one equivalent of the base cation (e.g. NaOH, KOH, NH 4 OH) and the salt is isolated from the aqueous phase by concentration or freeze-drying.

The racemic 6-fluoro-spiro [4H-1-benzopyran-4,4'-imidazoline-3 ', 5'-dione required for the process of the present invention is prepared from 6-fluoro-4-chromanone according to the method of Sarges, US Patent No. 4 The recovery of the overall process is greatly increased by isolating the enantiomer of sorbinil (usually also containing racemate) from the mother liquors. This was recycled through 6-fluoro-4-chromanone and another racemate was prepared suitable for the optical resolution of sorbinil.

The present invention is illustrated by the following examples. However, it is to be understood that the invention is not limited to certain details in these examples.

Example 1

Sorbinil over (-) - 3-aminomethylpinan salt (-) - 3-aminomethylpinan hydrochloride, 9.5 g (46.6 mmol), ethyl acetate (186 mL) and 1N

NaOH (93 mL) was stirred vigorously for 10 minutes. The organic phase is separated, washed once with 93 ml of water, dried over magnesium sulphate and stripped to give (-) - 3-aminomethylpinan free base as an oil 7.75 g (99%) = -54.85 (c = 1, methanol) which is then dissolved in 20 ml of methanol.

Racemic 6-fluoro-spiroE4H-1-benzopyran-4,4'-imidazolidine-3,5'-dione (10.0 g, 42.3 mmol) was dissolved in 214 mL of 2-propanol and 194 mL of methanol, heated to boiling The above-prepared amine solution is added to the solution under reflux and a clear solution is obtained at a boiling point of 71 ° C. The solution was slowly cooled (crystallization started at 27 ° C) and stirred at room temperature for 6 hours. The crude (-) - 3-aminomethylpinane salt of sorbinil was isolated by filtration. After drying under vacuum at 40 ° C, 6.81 g, m.p. 127.5-196 ° C (dec.).

= 8.2 ° (c = 1, methanol). Yield 79.6%. The mother liquors are evaporated to dryness to give the crude (-) - 3-aminomethylpinan salt of sorbinil enantiomer, the main ingredient being the (-) - 3-aminomethylpinan salt of sorbinil.

The crude sorbinil salt (6.7 g) was dissolved at boiling point in 80.4 ml of a 1: 1 mixture of methanol and isopropanol, slowly cooled to room temperature, and the resulting solids were granulated for 2 hours. The purified salt was collected by filtration, washed with 4 mL of 1: 1 methanol: isopropanol and dried in vacuo at 40 ° C. Yield 4.42 g, m.p. 119 DEG-208 DEG C. (decomposition), [.alpha.] D + 3.9 DEG (c = 1, methanol). Yield = 66%.

The purified salt (4.33 g, 10.7 mmol) was shaken in a mixture of 107.5 mL of ethyl acetate and 53.8 mL of 1N hydrochloric acid. The organic phase is separated, washed once with 54 ml of 1N hydrochloric acid, once with 54 ml of water and once with 54 ml of sodium chloride solution, dried over magnesium sulphate, filtered, evaporated in vacuo to a slurry which is evaporated three times with 50 ml of ethyl acetate to a final volume of 12 ml. , granulated for 3 hours, filtered and dried in vacuo at 40 ° C. Yield of sorbinil 2.18 g, mp 234-242 ° C, η ⁵ - + 51.2 ° (c = 1, methanol). Yield 86.2%. Alternatively, the dry organic phase is extracted with an equivalent of 1N NaOH. The extract was separated and freeze-dried to the sorbinil sodium salt.

CS 266 560 B2

The above prepared aqueous layers from sorbinil isolation (226 ml) were combined with 113 ml of dichloromethane and the pH adjusted to 10.0 with 25% NaOH. The aqueous phase is separated and extracted with 55 ml of fresh dichloromethane. The dichloromethane phase was combined, evaporated to 60 ml in vaktta, washed once with water (1 ml), dried over magnesium sulfate and evaporated. There was obtained (-) [beta] -aminomethylpinane as an oil, 1.58 [.alpha.] D -55.5 DEG (c-1, methanol).

Sorbinil is further purified by dissolving in 20 ml of hot ethanol, concentrating to 1/2 volume and granulating at room temperature for 4 hours. The purified sorbinil is filtered off and dried under vacuum at 40 ° C. 1.82 g, mp 234-241.5 [deg.] C. < ⁵ > Yield 91 Overall yield 41.2%.

SUBJECT VYNALEZU A process for preparing sorbinil of formula AND 0 HN --- 1 F _x HIVE· or a pharmaceutically acceptable cationic salt thereof characterized by:

Claims (1)

a) crystallizes the (-) - 3-aminomethylpinan salt of sorbinil from a solution of racemic hydantoin of formula II b) converting the aminopinate salt to sorbinil or a pharmaceutically acceptable salt thereof. Severografla, n. P., MOST