IL141690A - Process for preparation of rasagiline and its salts - Google Patents

Abstract

A process for the optical resolution of racemic N-benzyl-1-indanamine, characterized in that it is carried out using (R, R)-tartaric acid as the optical resolving agent, to form N-benzyl-l-indanamine (R, R)-tartrate. 1512 א' בתמוז התשס" ד - June 20, 2004

Description

141690/2 Process for preparation of rasagiline and its salts International Specialty Products (Israel) 0*Ί\ί») twp-ma ob\y>a > l». y.i03N Ltd.

C.131795 PROCESS FOR PREPARATION OF RASAGILINE AND ITS SALTS FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of (R)-l-indanamine derivatives, in particular rasagiline and precursor thereof, and also to novel intermediates used in this process and to preparation thereof.

BACKGROUND OF THE INVENTION Rasagiline, (R)-N-propargyl-l-indanamine, having the formula: and its salts are potent, selective, irreversible inhibitors of the enzyme monoamine oxidase type B (MAO-B) which may be used for treatment of Parkinson's disease (U. S. Patent No. 5,786,390).

Teva Pharmaceutical Ind. in Org. Prep. Proced. Int., 1997, v. 29, 701 and U. S. Patents No. 5,786,390 and 5,994,408 provides a process for the preparation of rasagiline or its salts starting from indene, which process comprises the steps Γ of: (a) adding of hydrogen chloride to indene to give 1-chloroindene; (b) reacting the 1-chloroindene of step (a) with benzylamine in toluene to give racemic N-benzyl- 1 -indanamine; (c) mixing racemic N-benzyl-l-indanamine with (S)-mandelic acid in absolute ethanol; (d) cooling the mixture of step (c) to form salt of (R)-enantiomerically enriched N-benzyl-l-indanamine with (S)-mandelic acid in solid form; (e) filtering off the precipitated solid of step (d) and, optionally, recrystallizing the solid; (f) isolating (S)-enantiomerically enriched N-benzyl-l-indanamine from the mother liqueur of step (e); (g) racemizing of the (S)-enantiomerically enriched amine from step (f) and recycling the racemized amine to step (c); (h) mixing the solid product of step (e) with aqueous NaOH and separating (R)-enantiomerically enriched N-benzyl-l-indanamine from aqueous solution of sodium (S)-mandelate; (i) hydrogenating under catalytic conditions (R)-enantiomerically enriched N-benzy 1- 1 -indanamine of step (h) in the presence of acid; (j) basifying the reaction mixture of step (i) with aqueous base and isolating (R)-enantiomerically enriched 1 -indanamine from the obtained mixture; (k) reacting the (R)-enantiomerically enriched 1 -indanamine of step (j) with propargyl chloride, bromide or sulfonate ester in the presence of base to give rasagiline; (1) reacting of rasagiline of step (k) with appropriate acid to give rasagiline salt.

For economical reasons, recycling processes should be organized in the above process for recovering of expensive resolving agent, (S)-mandelic acid, and solvent, absolute ethanol.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel process for the preparation of rasagiline or its salts, in particular rasagiline mesylate, which excludes the use of expensive resolving agents and solvents.

The above object is achieved in accordance with the present invention which, in one aspect thereof, provides a process for the optical resolution of racemic N-benzyl-l-indanamine, characterised in that it is carried out using (R,R)-tartaric acid as the optical resolution agent, to form N-benzyl-l-indanamine (R,R)-tartrate.

More specifically, the process of the invention comprises: (a) reacting of racemic N-benzyl-l-indanamine with (R,R)-tartaric acid in water; (b) cooling the mixture of step (a) to form a salt of (R)-enantiomerically enriched N-benzyl-l-indanamine with (R,R)-tartaric acid in solid form; (c) separating said solid salt obtained in step (b); and (d) mixing the solid product of step (c) with water and base and isolating (R)-enantiomerically enriched N-benzyl-l-indanamine from the obtained mixture.

The above process may be used in the preparation of rasagiline or its salts, in particular rasagiline mesylate, which process comprises the steps of: (a) reacting of racemic N-benzyl-l-indanamine with (R,R)-tartaric acid in water; (b) cooling the mixture of step (a) to form salt of (R)-enantiomerically enriched N-benzyl-l-indanamine with (R,R)-tartaric acid in solid form; (c) separating said precipitated solid and, optionally, recrystallizing the solid; (d) basifying the mother liqueur of step (c) and isolating (S)-enantiomerically enriched N-benzyl-l-indanamine from the obtained mixture; (e) racemizing of the (S)-enantiomerically enriched amine from step (f); (f) recycling the racemized amine to step (a); (g) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts; 141690/1 - 3a - (h) basifying the reaction mixture of step (g) with aqueous base and isolating (R)-enantiomerically enriched 1 -indanamine from the obtained mixture; (i) converting the (R)-enantiomerically enriched 1 -indanamine of step (g) to rasagiline or its salts.

In accordance with a further aspect of this invention, there is provided a novel compound which is a salt of (R)-enantiomerically enriched N-benz l-1 -indanamine and (R,R)-tartaric acid. The novel intermediate of the present invention is a stable, solid compound, obtainable in high yield, which can be easily purified by crystallization and stored for long periods of time. - 4 - DET AILED DESCRIPTION OF THE INVENTION The invention provides, inter alia, a process for the optical resolution of racemic N-benzyl-l-indanamine, characterised in that it is carried out using (R,R)-tartaric acid as the optical resolution agent. Preferably, the process comprises a step of fractional crystallization of N-benzyl-l-indanamine (R,R)-tartrate. Preferably, the process is carried out in aqueous medium. Preferably, the racemic N-benzyl-l-indanamine/(R,R)-tartaric acid molar ratio in the process is between 1 :0.5 and 1 :2. More preferably, the molar ratio is between 1 :1.

Preferably, the process for the optical resolution of racemic N-benzyl-l-indanamine comprises the steps of: (a) reacting of racemic N-benzyl-l-indanamine with (R,R)-tartaric acid in water; (b) cooling the mixture of step (a) to form a salt of (R)-enantiomerically enriched N-benzyl-l-indanamine with (R,R)-tartaric acid in solid form; (c) separating said precipitated solid and, optionally, recrystallizing the salt; (d) basifying the mother liqueur of step (c) and isolating (S)-enantiomerically enriched N-benzyl-l-indanamine from the obtained mixture; (e) racemizing the (S)-enantiomerically enriched amine obtained in step (f); (f) recycling the racemized amine to step (a); (g) mixing the solid product of step (c) with water and base and isolating (R)-enantiomerically enriched N-benzyl-l-indanamine from the obtained mixture. Racemic N-benzyl-l-indanamine may be prepared by reductive amination of 1-indanone with benzylamine or N-alkylation of benzylamine with 1-chloroindan.

The unwanted isomer of N-benzyl-l-indanamine may be racemized in high yield in the presence of strong base or by the method, described in Org. - 5 - Prep. Proced. Int., 1997, v. 29, 701.

(R) and (S)-N-benzyl-l-indanamines have low absolute value of specific rotations determined at sodium D-line. For determination of enantiomeric purity of (R) and (S)-N-benzyl-l-indanamine said compounds were transformed to N-nitroso derivatives with substantially higher absolute value of specific rotations measured at sodium D-line.

A solid salt of (R)-enantiomerically enriched N-benzyl-l-indanamine and (R,R)-tartaric acid is a new compound and it was shown in this invention that the salt may be effectively used for the preparation of rasagiline or its salts.

The present invention also provides a new effective process for the preparation of rasagiline or its salts, in particular rasagiline mesylate, which process comprises the steps of: (a) reacting of racemic N-benzyl-l-indanamine with (R,R)-tartaric acid in water; (b) cooling the mixture of step (a) to form salt of (R)-enantiomerically enriched N-benzyl-l-indanamine with (R,R)-tartaric acid in solid form; (c) separating said precipitated solid and, optionally, recrystallizing the solid; (d) basifying the mother liqueur of step (c) and isolating (S)-enantiomerically enriched N-benzyl-l-indanamine from the obtained mixture; (e) racemizing of the (S)-enantiomerically enriched amine from step (f); (f) recycling the racemized amine to step (a); (g) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts; (h) basifying the reaction mixture of step (g) with aqueous base and isolating (R)-enantiomerically enriched 1-indanamine from the obtained mixture; (i) converting the (R)-enantiomerically enriched 1-indanamine of step (g) to rasagiline or its salts. - 6 - It should be noted that in the known process, described in Org. Prep. Proced. Int., 1997, v. 29, 701 and U. S. Patents No. 5,786,390 and 5,994,408, mandelic acid is subjected to process of hydrogeno lysis under condition of catalytic hydrogenation. So it is undesirable to subject (R)-N-benzyl-l-indanamine (S)-mandelate to N-debenzylating without preliminary isolation of (R)-N-benzyl-l-indanamine from the salt. On the opposite, tartaric acid, which is the resolving agent used in the present invention, is not involved in any undesirable processes under condition of catalytic hydrogenation. So there are no obstacles to N-debenzylating (R)-N-benzyl-l-indanamine (R,R)-tartrate without preliminary isolation of (R)-N-benzyl-l-indanamine base from the salt.

This invention will be better understood from the Examples that follow. However, the examples illustrate, but do not limit, the invention. Those skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims that follow thereafter. - 7 - Example 1 Preparation of racemic N-benzyl- 1 -indanamine A mixture of 1-indanone (2200.0 g, 16.6 mol), benzylamine (2005 mL, 18.7 mol) 63 g (1.05 mol) of acetic acid and benzene (6.0 L) was stirred under reflux conditions for 4 hours in an apparatus equipped with Dean-Stark trap. After 299 mL (16.6 mol) water were collected, the reaction mixture was cooled under argon to 20 °C, washed (3 x 1) with ice water and concentrated under reduced pressure at 50 - 60 °C to half a volume. The residue was added to a stirred solution of sodium borohydride (344.0 g, 9.0 mol) in abs. ethanol (10.0 L) at room temperature. The mixture was stirred for 24 hours at room temperature and treated with 10 % aq. NaOH (1.0 L). Benzene and ethanol were evaporated under reduced pressure at 50 - 60 °C from the mixture. The residue was extracted with heptane. The combined organic extracts were dried over sodium carbonate, filtered and concentrated under reduced pressure at 50 - 60 °C. The residue was fractionally rectified under pressure of 1 mbar. N-Benzyl-1 -indanamine (3040.0 g, 82 %) was collected in the fractions of bp 125 - 135 °C, with 95.9 % purity by GC. - 8 - Example 2 Preparation of racemic N-benzyl-l-indanamine 1-Chloroindan (15.0 g, 98.3 mmol) was added to a stirred solution of benzylamine (30.0 g, 250 mmol) in acetonitrile (150 mL) at room temperature. The mixture was stirred for 2 hours under reflux conditions and 1 hour at room temperature. The precipitated crystals were filtered off, washed on filter with acetonitrile (20 mL) and dried at 50 - 60 °C under reduced pressure to give 14.0 g (97.5 mmol) of benzylamine hydrochloride. The mother liquors were collected and concentrated under reduced pressure at 50 - 60 °C. A solution of the residue in heptane (50 mL) was washed with water (20 mL), dried over sodium carbonate, filtered and concentrated under reduced pressure at 50 - 60 °C. The residue was fractionally rectified under pressure of 1 mbar. N-Benzyl-l-indanamine (14.0 g, 64 %) was collected in the fractions of bp 125 -135 °C. - 9 - Example 3 Preparation of (R)-N-benzyl-l-indanamine (R,R)-tartrate N-Benzyl-l-aminoindan (917.0 g, 4.1 mol) was added to a stirred solution of (R,R)-tartaric acid (675.0 g, 4.5 mol) in water (21 L) at 70 - 80 °C. The mixture was stirred for 0.5 hour at the same temperature and left without stirring for 48 hours at room temperature. The precipitated coarse crystals were filtered off, washed on filter with water (0.5 L) and dichloromethane (1 L) and dried under reduced pressure at 50 - 60 °C to a constant weight to give 619.0 g (40 %) of (R)-enantiomerically enriched N-benzyl-l-indanamine (R,R)-tartrate with [ab20 (free base) 3.0° (c 4.75, abs. ethanol), ee -75 %. The crystals (618.0 g) were dissolved in boiling water (8.5 L) and the solution was kept for 48 hours at room temperature. The precipitated crystals were filtered off, washed on filter with water (300 mL) and dichloromethane (0.5 L), and dried under reduced pressure at 50 - 60 °C to a constant weight to give 490.0 g (32 %) of (R)-N-benzyl-l-indanamine (R,R)-tartrate with mp 135-144 °C (dec.) and [a (free base) 4.0° (c 5.34, abs. ethanol).

The organic layer was separated from the combined mother liquors of the crystallization steps. The aqueous layer was basified by 40 % aq. NaOH to pH 12 and extracted with dichloromethane (2 x 4 L). The combined organic extracts were dried over sodium carbonate, filtered and evaporated under reduced pressure at 50 - 60 °C to give 574 g (62.5 %) of (S)-enantiomerically enriched N-ben2yl-l-indanamine with [ ]ϋ 20 -1 -5° (c 5, abs. ethanol), ee ~37.5 %. - 10 - Example 4 Racemization of (S)-N-benzyl-l-indanamine 20 A mixture of (S)-N-benzyl-l-indanamine (38.9 g, 170 mmol) {[ ]υ -4.2° (c 5, abs. ethanol)}, potassium tert-butoxide (4.0 g, 35.6 mmol) and anhydrous DMSO (40 mL) was stirred in argon atmosphere for 2 hours at 120 °C (oil bath). Water (200 mL) was added to the stirred mixture at room temperature and the product was extracted with heptane (3 x 100 mL). The combined organic layer was washed with water (200 mL), dried over sodium sulfate and filtered. After evaporation of the solvent under reduced pressure at 50 - 60 °C (water bath), the residue was fractionally rectified under pressure of 1 mbar. N-Benzyl-l-indanamine (31 ,0 g, 80 %) with [CI]D20 -0.1±0.1° (C 5, abs. ethanol) was collected in the fractions of bp 125 - 135 °C.

Example 5 Preparation of N-nitroso derivatives of enantiomerically enriched N -benzyl- 1 -indanamines (R)-N-benzyl-l-indanamine (1.5 g, 6.7 mmol) {[ ]ϋ2° 4.0° (c 5.34, abs. ethanol)} was dissolved in a solution of citric acid (1.0 g, 5.2 mmol) in water (10 mL). A solution of sodium nitrite (0.7 g, 10.1 mmol) in water (2 mL) was added dropwise to the stirred solution obtained above at 0 - 10 °C (ice/water bath). The mixture was stirred for 0.5 hour at 15 - 20 °C and extracted with dichloromethane (3 x 5 mL). The combined organic extracts were washed with water (5 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure at 50 -60 °C (water bath) to give (R)-N-benzyl-N-nitroso-l-indanamine (90-95 % yield) with [ ]ϋ2° +66±2° (c 2, abs. ethanol). - 12 - Example 7 Preparation of (R)-l-indanamine A mixture of (R)-N-benzyl-l-indanamine (R,R)-tartrate (500.0 g, 1.34 mol), 5 % palladium on carbon powder (Johnson Matthey type 487, 25.0 g) and distilled water (5 L) was stirred in a stainless steel reactor for 1 hour at 45 - 50 °C under 25 atm of hydrogen pressure. The reaction mixture was filtered, washed with dichloromethane (3 L), basified with 32 % aq. NaOH to pH 12 and extracted with dichloromethane (2 x 1 L). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure at 50 - 60 °C (water bath). The residue was fractionally distilled under pressure of 26 mbar. (R)-1-Indanamine (128.5 g, 72 %) with [Ο.]Ώ ° -16° (c 2.7, methanol) was collected in the fractions of bp 130 - 140 °C. - 13 - Example 8 Preparation of (R)-l-indanamine A mixture of (R)-N-benzyl-l-indanamine (248.0 g, 1.11 mol), glacial acetic acid (100 mL, 1.75 mol), 0.65 mol sodium acetate, 10 % palladium on carbon powder (25.0 g) and methanol (5 L) was stirred in a stainless steel reactor at 45 - 50 °C under 20 atm of hydrogen pressure. The reaction was controlled by GC and the conversion was not higher than 95-97 % to avoid the hydrogenolysis of the 1-indanamine formed. The reaction mixture was filtered and concentrated under reduced pressure at 50 - 60 °C (water bath). A solution of the residue in water (2.5 L) was basified with 32 % aq. NaOH to pH 12 and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure at 50 - 60 °C (water bath). The residue was fractionally rectified under pressure of 10 mbar. (R)-1-Indanamine (120.3 g, 81 %) with [α]ϋ2° -16° (c 1.5, methanol) was collected in the fractions of bp 118 - 122 °C.

Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

Claims (12)

14 1 690/2 1 5 C L A I M S:

1. A process for the optical resolution of racemic N-benzyl- 1-mdanmiiine, characterized in that it is carried out using (R.R)-tartaric acid as the optical resolving agent, to form N-benzyl- l- danamine (R,R)-tartrate.

2. The process according to claim 1, characterized in that the reaction is carried out in aqueous medium.

3. The process according to claim 1, characterized in that the molar ratio between racemic N-benzyl-l-mdanarnine and (R,R)-tartaric acid is between 1 :0.5 and 1 :2.

4. The process according to claim 3, characterized in that the molar ratio between racernic N-benzyl- l-indanainme and (R,R)-tartaric acid is about 1 :1.

5. A process for the optical resolution of racemic N-benzyl-l-mdanarnine, comprising: (a) reacting racemic N-benzyl- 1 -indanamine with (R,R)-tartaric acid in water; (b) cooling the mixture of step (a) to form a salt of (R)-enantiomerically enriched N-benzyl-l -indanamine with (R,R)-tartaric acid in solid form; (c) separating said solid, salt obtained in step (b); and (d) niixing the solid product of step (c) with water and base and isolating (R)-enantiomerically enriched N-benzyl- 1 -mdanamine from the obtained mixture.

6. The process according to claim 5 further comprising a step of fractional crystallization ofN-benzyl-1 -indanamine (R,R)-tartrate after step (c).

7. The process according to claim 5, further comprising the following steps after step (c) and before step (d): (ci) basifying the mother hquour of step (c) and isolating (S)-enantiomericaHy enriched N-benzyl- l-indanamine from the obtained mixture; (cii) racemizing the (S)-enantiomerically enriched amine obtained in step (ci); (ciii) recycling the racemized amine to step (a):

8. 5. A salt of (R)-enantiomerically enriched N-benzyl- 1 -mdanamine Avith (R,R)-tartaric acid. 141690/2 16

9. .A salt of (R)-enantiomeri.caily enriched N-bcnzyl- 1 -indanamine with. acid for use jjn the preparation of rasagiline or its salts.

10. A process, for the preparation of rasagiline or its salts comprising: (a) reacting r&cemic N-benzyl- 1 -indanamine with (RjRJ-tartaric acid ijn. water; (b) cooling tft.e mixture of step (a) to form a salt of (R)-enantiorD.erically enriched N-benz !-l-indanamine with (R,R)-tartaric acid in solid form.; (c) separating said precipitated solid salt obtained in step (b); (d) hydrogeniting under catalytic conditions the solid product of step (c), optionally, in.thei presen.ee of acids, bases or salts; (e) basif ing ithe reaction mixture of step (d) with, aqueous base and isolating (R)-enantiomeriCally enriched J.-ind^amine from the obtained mixture; and (f) converting the (R)-enantiomerically enriched 1-indanarhine of step (e) to ' rasagiline or its salts.

11. The process according to claim 10, further comprising the following steps after step (c) andl before step (d): (ci.) basifying the mother liqueur of step (c) and isolating (S)-enantiomericaliy enriched N-benzyl- 1 -indanamine from the obtained mixture; (cii) racemizing the (S)-enantiomerically enriched amine obtained in step (ci); (ciii) recycling the racemized amine to step (a).

12. The process according to claim 10 further comprising a step of fractional crystallization of N-benzyl- -indanamine (R_R)-tar ra.te after step (c). For the Applicants, REINHOLD COHN AND PARTNERS