FI77247C - Process for the preparation of sorbinil or its salt and in the process useful intermediate. - Google Patents

Description

1 77247

Process for the preparation of sorbinil or a salt thereof and an intermediate used in the process

The invention relates to a process for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof.

S-6-fluorospiro [chromane-4,4'-imidazolidine) -2 ', 5'-dione, also known as S-2,3-dihydro-6-fluorospiro [4H-1-benzopyran-4, 4'-imidazolidin-10-yl) -2 ', 51-dione (USAN: sorbinil), and having a ca- (<5) H ^ f0 A <15 ^ | (5) is a highly potent aldose reductase inhibitor, which is particularly valuable in the effective treatment of chronic complications of diabetes mellitus (Sarges, U.S. Patent 4,130,714).

In addition, the invention is directed to novel intermediates used in this new process.

Previously, sorbinil has been prepared by partitioning the optically corresponding racemic 6-fluorospiro (chromane-4,4'-imidazolidine) -2 ', 51-dione of formula (3) HM-f

30 F

ΌΟ 35 using highly toxic brucine in large amounts as a dividing agent (U.S. Patent 4,130,714).

2 77247

Surprisingly, it has now been found that the optical resolution of the racemate can be performed with the (-) - 3-aminomethyl-pinane salt of sorbinil. Good yields of sorbinil are obtained with considerably smaller amounts of solution and at the same time the use of a highly toxic optically resolving agent is avoided. The efficiency of this method can be further improved by isolating the undesired enantiomers from the mother liquors and returning them to the fresh racemate via the 6-fluoro-4-chromanone precursor.

Sorbinil has also recently been prepared by alternative synthesis, in which the required optical isomerism is induced during a series of syntheses (Sarges, U.S. Patent 4,286,098).

The process according to the invention for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof is characterized in that a) the (-) - 3-aminomethylpinane salt of sorbinil is crystallized by cooling and then stirring at ambient temperature a hot solution of substantially 20 equimolar amounts of racemic hydantoin,

HN L

And (-) - 3-aminomethylpinane in a substantially 1: 1 mixture of 2-propanol and methanol, and b) said aminopinane salt is converted to sorbinil or a pharmaceutically acceptable salt thereof.

The optically isomeric (-) - 3-aminomethylpinane salt of sorbinil useful as an intermediate of the invention can be isolated in crystalline form.

35 3-Aminomethylpinan has the following formula E r-3 77247

The method according to the invention can be described by the following diagram:

Scheme 5 η ~ Χ ° 7 ~ f ° (3) (5) sorbinil 15

The term "cationic salt" includes alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), and salts with amines (e.g., ammonia).

The method of the present invention is easily performed. To prepare sorbinil by direct optical partitioning, the racemate is slurried or dissolved in a solvent, suitably a lower alkanol or a mixture of lower alkanols, and heated to 50-25 ° C. The preferred solvent is a 1: 1 v / v mixture of methanol and isopropanol suitably heated to reflux (about 69-71 ° C). A substantially molar equivalent of (-) - 3-aminomethylpinan, suitably dissolved in a portion of the solvent, is added to the hot slurry or solution to form diastereomeric salts. The amine salt solution is slowly cooled to about 0-5 ° C and the crystalline solids formed are usually granulated for some time before isolation. This slow cooling and granulation minimizes the formation of inclusions of the undesirable diastereomeric salt. The volume of solvent is selected to maximize the recovery of the sorbinil salt while minimizing the amount of undesirable enantiomeric salt that crystallizes. If the product contains a significant amount of the latter, it can be easily removed by recrystallization from the same alkanol or mixture of alkanol solvents, if necessary. The (-) - 3-aminomethyl-5-pinane salt of sorbinil is then converted to sorbinil or a pharmaceutically acceptable salt thereof by standard methods known in the art. For example, the amine salt is partitioned between at least one equivalent of aqueous acid and a water-immiscible organic solvent, and sor-10 binyl is recovered by separating and concentrating the organic layer and / or adding a non-solvent. If a pharmaceutically acceptable cationic salt is desired, the sorbinil is re-extracted into water containing approximately one equivalent of the cation in base form (e.g. NaOH, KOH, NH 3 OH) and the salt is isolated from the aqueous layer by concentration or freeze-drying.

The racemic 6-fluorospiro [4H-1-benzopyran-4,4'-imidazolidine) -2 ', 5'-dione required in the sorbinil process of the invention is derived from 6-fluoro-4-20 chromanone according to the method of Sarges. U.S. Patent No. 4,130,714. The efficiency of the overall process is greatly increased when the enantiomer of sorbinil (which usually also contains the racemate) is recovered from the mother liquor. The latter is recovered via 6-fluoro-4-chromanone to form an additional racemate suitable for optical resolution of sorbinil. The recoverable 6-fluoro-4-chromanone is regenerated.

The optically divided salt is converted to its acid form, if desired, by standard methods, acidification and extraction. The optically resolving agent is recovered from the aqueous raffinate, if desired, by standard methods such as basification and extraction.

The optically resolving free acid or suitably its amine salt is readily converted to sorbinil by heating to 35-110 ° C in glacial acetic acid. This step is suitably carried out in a steam bath at 90 to 100 ° C.

5 77247

The present invention is illustrated by the following example. All temperatures are in degrees Celsius. Unless otherwise noted, temperatures are ambient temperatures. Unless otherwise stated, the solvent removal 5 takes place in vacuo.

Example

Sorbinil via its (-) - 3-aminomethylpinane salt 9.5 g (46.6 mmol) of (-) - 3-aminomethylpinan-10 hydrochloride, 286 ml of ethyl acetate and 93 ml of 1N sodium hydroxide solution were stirred vigorously for 10 minutes. The organic layer was separated, washed once with 93 ml of water, dried over magnesium sulfate and concentrated to give (-) - 3-aminomethylpina-15 free base as an oil; 7.75 g (99%); = -54.85 ° (c = 1 in methanol); which was then dissolved in 20 ml of methanol.

Racemic 6-fluoro spiro- (4H-benzopyran-4,4'-imidazolidine) -2 ', 5'-dione (10.0 g, 42.3 mmol) was dissolved in 214 mL of 2-propanol and 194 mL of: methanol, was heated to reflux and the above amine solution was added to form a clear solution at 71 ° C. The solution was slowly cooled (crystallization began at 27 ° C) and stirred at room temperature for 6 hours. The crude sorbinil (-) - 3-aminomethylpinane salt was collected by filtration and dried in vacuo at 40 ° C; yield 6.81 g; mp. 127.5-196 ° C (dec.); = -8.2 ° (c = 1 in methanol). The yield of the phase was 79.6%. Its mother liquor 30 was evaporated to dryness to give the crude (-) - 3-aminomethylpinane salt of the enantiomer of sorbinil, the major impurity being the (-) - 3-aminomethylpinane salt of sorbinil.

The crude sorbinil salt (6.7 g) was dissolved in 80.4 ml of a 1: 1 methanol / isopropanol mixture under reflux, slowly cooled to room temperature and the resulting solid was granulated for 2,677247 hours. The purified salt was collected by filtration together with 4 ml of a 1: 1 methanol / isopropanol wash and dried in vacuo at 40 ° C; yield 4.42 g; mp. 119-208 ° C (dec.); Δ (S = J = 3.9 ° (c = 1 in methanol); step yield 66%.

The purified salt (4.33 g, 10.7 mmol) was partitioned between 107.5 mL of ethyl acetate and 53.8 mL of 1 N hydrochloric acid. The organic layer was separated, washed once with 54 ml of 1N hydrochloric acid, once with 54 ml of water and once with 54 ml of brine, dried over magnesium sulphate, filtered, evaporated in vacuo to a slurry of 12 ml to a final volume of 3 x 50 ml: 11a ethyl acetate, granulated for 3 hours, filtered and dried in vacuo at 40 ° C to give sorbinil; 2.18 g; mp. 234-242 ° C; s * N 2 O 5 = + 51.2 ° (c = 1 in methanol); the yield of the phase was 86.2%.

Alternatively, the dried organic layer is extracted with 1 equivalent of 1 N sodium hydroxide-20 solution. The extract is separated and freeze-dried to give the sodium salt of sorbinil.

The above aqueous layers from the sorbinil recovery were combined (226 mL), 113 mL of Cl 2 Cl 2 was added, and the pH was adjusted to 10.0 with 25% sodium hydroxide solution. The aqueous layer was separated and extracted with 55 mL of fresh CH 2 Cl 2. The CH 2 Cl 2 layers were combined, evaporated in vacuo to 60 ml, washed once with 30 ml of water, dried over magnesium sulphate and evaporated to give (-) - 3-amino-2-methylpinan as an oil; yield 1.58 g; (p <1 JD = -55.5 (c = 1 in methanol).

Sorbinil was further purified by dissolving in 20 ml of hot ethanol, concentrating to half volume and granulating for 4 hours at room temperature. The purified sorbinil was collected by filtration and dried at 40 ° C; yield 1.82 g; mp. 234-241.5 ° C; = + 53.1 °; phase yield 91%. The overall yield was 41.2%.

Claims (2)

777247 Using the same extraction procedure described above, the above crude (-) - 3-aminomethylpinane salt of the sorbinil enantiomer was converted to (-) - 3-aminomethylpinane suitable for recovery and the enantiomer of sorbinil 5 contaminated with racemate. A process for preparing sorbinil or a pharmaceutically acceptable cationic salt thereof, characterized in that a) the (-) - 3-aminomethylpinane salt of sorbinil is crystallized by cooling and then stirring at ambient temperature a hot solution containing substantially equimolar amounts of racemic hydantoin, of the formula -NH 25 3a (“) -3-aminomethylpinane in a substantially 1: 1 mixture of 2-propanol and methanol, and b) converting said aminopinane salt to sorbinil or a pharmaceutically acceptable salt thereof. 2. The chiral (-) - 3-aminomethylpinane salt of sorbinil.