NO161916B - PROCEDURE FOR SORBINIL PREPARATION. - Google Patents

Description

S-6-fluorospiro[chromane-4,4'-imidazolidine]-2',5'-dione, also called S-2,3-dihydro-6-fluorospiro-[4H-1-benzopyran-4,4'- imidazolidine]-2',5'-dione (U.S.A.N.: sorbinyl) of formula I:

is a powerful inhibitor of aldose reductase which has particular value when it comes to effective control of the chronic complications of diabetes mellitus. (Sarges, US patent no. 4,130,714. The present invention relates to an improved process for preparing sorbinil.

So far, sorbinil was prepared by dissolving the corresponding racemic 6-fluorospiro[4,4'-imidazolidine)-2',5'-dione of formula II:

by using highly toxic brucine as a solvent in high volumes of solvent (US Patent No. 4,130,714).

Surprisingly, we have found that sorbinil can be prepared by crystallizing the (-)-3-aminomethylpinan-, (-)-2-amino-2-norpinan- or quinine salt of sorbinil from a solution of racemic hydantoin of the formula in a solvent consisting of a lower alkanol or a mixture of lower alkanols where the racemate is slurried at 50-90"C and the amine salt is slowly cooled to 0-5<*>C; after which the resulting salt is converted to sorbinil or a pharmaceutically acceptable, cationic salt thereof. Good yields of sorbinil is achieved with much lower solvent volumes, and at the same time the use of highly toxic solvent is avoided. ;Sorbinil has also recently been prepared by an alternative synthesis in which the required chirality is induced through the synthetic sequence (Sarges, US Patent No. 4,286,098 ).;An embodiment of the present method for the preparation of sorbinil, or a pharmaceutically acceptable cationic salt thereof, consists in the steps: a) to crystallize (-)-3-aminoethylpina the n salt of sorbinil from a solution of racemic hydantoin of formula II; and b) converting said aminopinane salt to said sorbinil or pharmaceutically acceptable salt thereof. ;Another embodiment of the present method for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof comprises the following steps: a) crystallizing the (-)-2-amino-2-norpinane salt of the enantiomer of sorbinil from a solution of racemic hydantoin of formula II; b) isolating a concentrate of sorbinil from the mother liquor thereof; c) crystallizing the quinine salt of sorbinil from a solution of said sorbinil concentrate; and ;d) converting said quinine salt of sorbinil into said sorbinil or a pharmaceutically acceptable salt thereof. 3-aminomethylpinane and 2-amino-2-norpinane respectively have the following formulas: ;The term "cationic salt" includes, but is not ;limited to alkali metal salts (e.g. sodium, potassium), alkaline earth salts (e.g. calcium, magnesium ) and salts with amines (e.g. ammonia). In a preferred embodiment, the salt will be an optically active amine which was used in the solution of the racemate (II). The method according to the present invention is carried out quickly. To prepare sorbinil by direct solution, the racemate is slurried or dissolved in a solvent, suitably a lower alkanol or a mixture of lower alkanols, by heating to 50-90°C. The preferred solvent is a mixture of methanol and isopropanol, in a ratio of approx. 1:1 by volume, suitably heated to reflux (approx. 69-71 °C). In fact, one molar equivalent of (-)-3-aminomethylpinane suitably dissolved in a portion of the solvent is added to the hot slurry or solution to form a solution of diastereomeric salts. The amine salt solution is cooled slowly to approx. 0-5'C and the resulting crystalline solids are ordinary ice granulated for a time before isolation. Such slow cooling and granulation minimizes occlusion of the undesired diastereomeric salt. The volume of solvent is chosen to maximize recovery of sorbinyl salt, while minimizing the amount of the undesired enantiomeric salt that crystallizes. If the product contains any appreciable amount of the latter, it is readily removed by further recrystallization from the same alkanol or mixed alkanol solvent. The (-)-3-aminomethylpinane salt of sorbinil is then converted to sorbinil or a pharmaceutically acceptable salt thereof by standard methods. For example, the amine salt is partitioned between at least one equivalent of aqueous acid and a water-immiscible organic solvent, and sorbinil is recovered by separation and concentration of the organic layer and/or addition of a non-solvent. If a pharmaceutically acceptable cationic salt is desired, sorbinil is extracted back into water containing one equivalent of the cation in base form (eg, NaOH, KOH, NH 4 OH) and the salt is isolated from the aqueous layer by concentration or freeze drying. ;To prepare sorbinil by the so-called double-solvent technique, the first step of the process is completely analogous to the direct step, with the exception that the enantiomer of sorbinil is crystallized directly as the ;(-)-2-amino-2-norpinane salt, provided a morlut concentrate, of (-)-2-amino-2-norpinane salt of sorbinil. The concentrate is then converted by standard methods (as detailed above) into a partially dissolved concentrate of sorbinil. Sufficient resolution is now obtained so that it can be completely completed by crystallization of sorbinil as its quinine salt. The conditions used are essentially as described above, but quinine is now substituted for the aminopinane derivative, with approx. 4:1 isopropanol:methanol as the now preferred solvent. The quinine salt can also optionally be recrystallized as described above and finally converted to sorbinil by standard methods as described above. The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. All temperatures are in °C. Unless otherwise specified, temperatures are room temperatures. Where not stated otherwise, solvent evaporation is carried out in vacuum. ;EXAMPLE 1 ;Sorbinil via its (1)-3-aminomethylpinane salt. (-)-3-Aminomethylpinane HCl, 9.5 g (46.6 mmol), ethyl acetate (186 mL) and 1N NaOH (93 mL) were stirred vigorously for 10 minutes. ;The organic layer was separated, washed with 1 x 93 mL H 2 O, dried (MgSO 4 ) and evaporated to give (-)-3-aminomethylpinane free base as an oil, 7.75 g (99%) [a]<2 >)<5> = 54.85° (c = 1 in methanol), which was then dissolved in 20 ml of methanol. ;Racemic 6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidin]-2',5'-dione (10.0 g, 42.3 mmol) was dissolved in 214 mL of 2-propanol and 194 mL of methanol , heated to reflux, and the above solution of amine added, which gave clear solution at 71<*> at reflux temperature. The solution was slowly cooled (crystallization began at 27°) and stirred at room temperature for 6 hours. The crude (-)-3-aminomethylpinane salt of sorbinil was recovered by filtration and dried in vacuo at 40°, 6.81 g, m.p. 127.5-196° (dec.), [α]2.5 = 8.2° (c = 1 in methanol). Yield in the step: 79.6%. The mother liquor is evaporated to dryness to give crude

(-)-3-aminomethylpinane salt of the enantiomer of sorbinil, main

its content is the (-)-3-aminomethylpinane salt of sorbinil.

Crude sorbinyl salt (6.7 g) was dissolved at reflux i

80.4 ml of 1:1 methanol/isopropanol, slowly cooled to room temperature and the resulting solids were granulated for 2 hours. Purified salt was recovered by filtration with 4 ml of 1:1 methanol/isopropanol, slowly cooled to room temperature and the resulting solids were granulated for 2 hours. Purified salt was recovered by filtration with 4 mL 1:1 methanol:isopropanol wash, and dried in vacuo at 40°C, 4.42 g, m.p. 119-208°

(dec.), [a]<2>)<5> = +3.9° (c = 1 in methanol). Yield in the step: 66%.

Purified salt (4.33 g, 10.6 mmol) was partitioned into 107.5 mL ethyl acetate and 53.8 mL 1N HCl. The organic layer was separated, washed with 1 x 54 mL 1N HCl, 1 x 54 mL H 2 O, and 1 x 54 mL brine, dried (MgSO 4 ), filtered, evaporated in vacuo to a slurry, treated with 3 x 50 mL ethyl acetate to a final volume of 12 ml, granulated for 3 h, filtered and dried in vacuo at 40° to give sorbinil, 2.18 g, m.p. 234-242°,

[a]2)<5> = +51.2° (c = 1, methanol). Yield in the step: 86.2%. Alternatively, the organic layer is extracted with one equivalent of 1N NaOH. The extract is separated and freeze-dried to give the sodium salt of sorbinil.

The above aqueous layers of sorbinyl recovery were combined (226 ml), then combined with 113 ml of CH 2 Cl 2 and pH adjusted to 10.0 with 25% NaOH. The aqueous layer was separated and extracted with 55 mL fresh CH2Cl2- The CH2Cl2 layers were combined, evaporated in vacuo to 60 mL, washed with 1 x 30 mL H2O, dried (MgSO4) and evaporated to give recovered (-)-3- aminomethylpinane; oil, 1.58 g, [α]2)5 = -55.5° (c = 1, methanol).

Sorbinil was further purified by dissolving in 20 ml of hot ethanol, concentrated to 1/2 volume and granulated for 4 hours at room temperature. Purified sorbinil was recovered by filtration and dried at 40° in vacuo, 1.82 g, m.p. 234-241.5°,

[oc]2.5 = +53.1°. Yield in the step: 91%. Total dividend: 41.2%.

With the same extraction techniques as described above, the above-mentioned crude (-)-3-aminomethylpinane salt of the enantiomer of sorbinil is converted to (-)-3-aminomethylpinane, suitable for recycling, and to the enantiomer of sorbinil, along with the racemate.

EXAMPLE 2.

Sorbinil via its (-)- 2- amino- 2- norpinane and quinine salt.

Racemic 6-fluorospiro[4H-1-enzopyran-4,4'-imidazolidine]-2',5'-dione (25 g, 0.106 mol) was slurried in 250 mL isopropanol and 100 mL methanol and heated to reflux. A solution of

(-)-2-norpinane (14.73 g, 0.106 mol) in 150 mL methanol was added to the hot slurry over 16 minutes. Complete dissolution then occurred approx. 75 ml of the amine solution

was added. The solution was kept at reflux and then cooled slowly to 0.5°C. The resulting slurry was granulated for 2 hours and (-)-2-amino-2-norpinane salt of sorbinyl enantiomer recovered by filtration (with 25 ml of 1:1 isopropanol/methanol wash) and dried at 40°C in vacuo, 18.71 g,

m.p. 170-187°C, [α]2.5 = -24.3° (c = 1, methanol). Yield: 94.5% of the theoretical.

The combined mother liquor and wash (515 mL), containing the primary (-)-2-amino-2-norpinan salt of sorbinil, was concentrated in vacuo to 250 mL and diluted with 512 mL of ethyl acetate and 256 mL of 1N HCl. The organic layer was separated, washed with 1 x 256 mL fresh IN HCl, 1 x 256 mL brine,

dried (MgSO 4 ), evaporated to 100 mL in vacuo and the remaining ethyl acetate treated with 3 x 100 mL hexane to a final volume of 75 mL. The resulting slurry was granulated for 2 hours and filtered to give crude sorbinil, dried in vacuo at 40°C, 11.56 g, m.p. 225-237°C, [a]<2>,<5> = +28.5°. Yield in the step: 92.5%.

Crude sorbinil (11.44 g, 48.4 mmol) was slurried in 137 mL of isopropanol and heated to reflux. A solution of quinine trihydrate (18.3 g, 48.4 mmol) in 34.3 mL of methanol was added over 7 min, giving a clear solution, and reflux was continued for 5 min. The solution was cooled slowly to 0-5°C, granulated for 2 hours and the quinine salt of sorbinil recovered by filtration and dried at 40°C, 16.05 g, m.p. 113-122°C (dec.),

[cx]2.5 = -70.4°. Yield in the step: 77.9%.

In an optional step, the quinine salt of sorbinil (15.96 g) was recrystallized by dissolving in 79.8 mL of isopropanol at reflux, concentrated to 44 mL, slowly cooled to room temperature, diluted with 20 mL of isopropanol, cooled to 0-5°C, granulated for 2 hours, filtered and dried at 40°C in vacuum,

14.38 g, m.p. 110.5-122°C (dec.) [a]<2>,<5> = 71.0° (c = 1, methanol). Yield in the step: 90%.

The quinine salt of sorbinil (14.1 g, 25.1 mmol) was partitioned between 350 mL of ethyl acetate and 175 mL of 1N HCl. The ethyl acetate layer was separated, washed with 1 x 175 mL fresh IN HCl, 1 x 175 mL H 2 O and 1 x 175 mL brine, dried (MgSO 4 ), evaporated to 25 mL

in vacuo, treated with 3 x 50 ml ethyl acetate to a final volume of 20 ml, cooled to 0.5°C, granulated for 2 hours and sorbinil was recovered by filtration, 4.72 g, mp 241-246°C, [a]2)<5> = +54°C (c = 1, methanol). Yield in the step: 80%.

Total dividend: 39.1%.

Claims (1)

Process for the production of sorbinil or a pharmaceutically acceptable cationic salt thereof, characterized in that the (-)-3-aminomethylpinan-, (-)-2-amino-2-norpinan- or quinine salt of sorbinil is crystallized from a solution of racemic hydantoin with the formula in a solvent consisting of a lower alkanol or a mixture of lower alkanols where the racemate is slurried at 50-90°C and the amine salt is slowly cooled to 0-5°C; after which the obtained salt is converted into sorbinil or a pharmaceutically acceptable, cationic salt thereof.