WO2002068376A1 - Process for the preparation of rasagiline and its salts - Google Patents

Process for the preparation of rasagiline and its salts Download PDF

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Publication number
WO2002068376A1
WO2002068376A1 PCT/IB2002/000542 IB0200542W WO02068376A1 WO 2002068376 A1 WO2002068376 A1 WO 2002068376A1 IB 0200542 W IB0200542 W IB 0200542W WO 02068376 A1 WO02068376 A1 WO 02068376A1
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Prior art keywords
indanamine
benzyl
enantiomerically enriched
tartaric acid
salts
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PCT/IB2002/000542
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French (fr)
Inventor
Arie L. Gutman
Igor Zaltzman
Victor Ponomarev
Maxim Sotrihin
Gennady Nisnevich
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Finetech Laboratories Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation
    • C07C209/88—Separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a novel process for the preparation of (R)- 1-indanamine derivatives, in particular rasagiline and precursor thereof, and also to novel intermediates used in this process and to preparation thereof.
  • MAO-B monoamine oxidase type B
  • step (b) reacting the 1-chloroindene of step (a) with benzylamine in toluene to give racemic N-benzyl- 1-indanamine;
  • step (d) cooling the mixture of step (c) to form the salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (S)-mandelic acid in solid form;
  • step (e) filtering off the precipitated solid of step (d) and, optionally, recrystallizing the solid;
  • step (f) isolating (S)-enantiomerically enriched N-benzyl- 1-indanamine from the mother liquor of step (e); (g) racemizing of the (S)-enantiomerically enriched amine from step (f) and recycling the racemized amine to step (c);
  • step (h) mixing the solid product of step (e) with aqueous NaOH and separating
  • step (j) basifying the reaction mixture of step (i) with aqueous base and isolating
  • step (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;
  • the process for the optical resolution of racemic N-benzyl- 1-indanamine comprises the following steps:
  • step (b) cooling the mixture of step (a) to form a salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (R,R)-tartaric acid in solid form;
  • step (c) separating said precipitated solid salt obtained in step (b);
  • step (d) mixing the solid product of step (c) with water and base and isolating (R)-enantiomerically enriched N-benzyl- 1-indanamine from the obtained mixture.
  • N-Benzyl- 1-indanamine (R,R)-tartrate obtained in step (c) is optionally recrystallized .
  • the process of the invention further comprises the following steps after step (c) and before step (d): (ci) basifying the mother liquour of step (c) and isolating (S)-enantiomerically enriched N-benzyl- 1 -indanamine from the obtained mixture;
  • step (cii) racemizing the (S)-enantiomerically enriched amine obtained in step (ci); (ciii) recycling the racemized amine to step (a).
  • the present invention provides a process for preparing rasagiline or its salts, in particular rasagiline mesylate, which process comprises the steps of: (a) reacting of racemic N-benzyl- 1-indanamine with (R,R)-tartaric acid in water;
  • step (b) cooling the mixture of step (a) to form salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (R,R)-tartaric acid in solid form; (c) separating said precipitated solid salt obtained in step (b);
  • step (d) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts;
  • step (e) basifying the reaction mixture of step (d) with aqueous base and isolating (R)-enantiomerically enriched 1-indanamine from the obtained mixture; and (f) converting the (R)-enantiomerically enriched 1-indanamine of step (e) to rasagiline or its salts.
  • the process comprises a step of fractional crystallization of N-benzyl- 1-indanamine
  • the process of the present invention further comprising the following steps after step (c) and before step (d):
  • step (ci) basifying the mother liqueur of step (c) and isolating (S)-enantiomerically enriched N-benzyl- 1-indanamine from the obtained mixture; (cii) racemizing the (S)-enantiomerically enriched amine obtained in step (ci);
  • 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.
  • the invention provides, inter alia, 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. According to a preferred embodiment of the invention, the process is carried out in aqueous medium.
  • the molar ratio between the racemic N-benzyl- 1-indanamine and (R,R)-tartaric acid is between 1:0.5 and 1 :2. More preferably, the molar ratio is about 1:1.
  • N-benzyl- 1-indanamine comprises the following steps:
  • step (a) reacting of 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- 1-indanamine with (R,R)-tartaric acid in solid form;
  • step (c) separating said precipitated solid salt obtained in step (b); and(d) mixing the solid product of step (c) with water and base and isolating
  • step (R) (R)-enantiomerically enriched N-benzyl- 1-indanamine from the obtained mixture.
  • step (d) the process further comprising the following steps after step (c) and before step (d):
  • step (ci) basifying the mother liquour of step (c) and isolating (S)-enantiomerically enriched N-benzyl- 1-indanamine from the obtained mixture;
  • step (cii) racemizing the (S)-enantiomerically enriched amine obtained in step (ci); (ciii) recycling the racemized amine to step (a).
  • Racemic N-benzyl- 1-indanamine may be prepared by reductive amination of 1-indanone with benzylamine or N-alkylation of benzylamine with
  • the unwanted isomer of N-benzyl- 1-indanamine may be racemized in high yield in the presence of strong base or by the method described in Org. Prep.
  • a solid salt of (R)-enantiomerically enriched N-benzyl- 1-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 following steps:
  • step (a) reacting of racemic N-benzyl- 1-indanamine with (R,R)-tartaric acid in water; (b) cooling the mixture of step (a) to form the salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (R,R)-tartaric acid in solid form;
  • step (c) separating said precipitated solid salt obtained in step (b);
  • step (d) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts; (e) basifying the reaction mixture of step (d) with aqueous base and isolating (R)-enantiomerically enriched 1-indanamine from the obtained mixture; and (f) converting the (R)-enantiomerically enriched 1-indanamine of step (e) to rasagiline or its salts.
  • the process of the present invention further comprising steps (ci) to (ciii) mentioned above.
  • N-Benzyl-1-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 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-Benzyl-l-indanamine (31.0 g, 80 %) with [OJ D 20 -O.l ⁇ O.l 0 (c 5, abs. ethanol) was collected in the fractions of bp 125 - 135 °C.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a novel process for the preparation of rasagiline or its salts, in particular rasagiline mesylate, which process comprises the steps of : (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-1-indanamine with (R,R)-tartaric acid in solid form; (c) separating said precipitated solid obtained in step (b); (d) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts; (e) basifying the reaction mixture of step (d) with aqueous base and isolating (R)-enantiomerically enriched 1-indanamine from the obtained mixture; and (f) converting the (R)-enantiomerically enriched 1-indanamine of step (e) to rasagiline or its salts.

Description

PROCESS FOR THE PREPARATION OF RASAGILINE AND ITS
SALTS
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of (R)- 1-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- 1-indanamine, having the formula:
Figure imgf000002_0001
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 provide a process for the preparation of rasagiline or its salts starting from indene, which process comprises the steps 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- 1-indanamine with (S)-mandelic acid in absolute ethanol;
(d) cooling the mixture of step (c) to form the salt of (R)-enantiomerically enriched N-benzyl- 1-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- 1-indanamine from the mother liquor 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- 1-indanamine from aqueous solution of sodium (S)-mandelate; (i) hydrogenating under catalytic conditions (R)-enantiomerically enriched
N-benzyl- 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 steps are carried out in the above process for recovering the expensive resolving agent (S)-mandelic acid, and the solvent absolute ethanol. SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel process for the optical resolution of racemic N-benzyl- 1-indanamine. It is another 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 objects are achieved in accordance with the present invention which, in one aspect thereof, provides 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- 1-indanamine
(R,R)-tartrate.
Preferably, the process for the optical resolution of racemic N-benzyl- 1-indanamine comprises the following steps:
(a) reacting of 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- 1-indanamine with (R,R)-tartaric acid in solid form;
(c) separating said precipitated 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- 1-indanamine from the obtained mixture.
N-Benzyl- 1-indanamine (R,R)-tartrate obtained in step (c) is optionally recrystallized .According to a preferred embodiment, the process of the invention further comprises the following steps after step (c) and before step (d): (ci) basifying the mother liquour of step (c) and isolating (S)-enantiomerically 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).
According to a second aspect thereof, the present invention provides a process for preparing rasagiline or its salts, in particular rasagiline mesylate, which process comprises the steps of: (a) reacting of racemic N-benzyl- 1-indanamine with (R,R)-tartaric acid in water;
(b) cooling the mixture of step (a) to form salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (R,R)-tartaric acid in solid form; (c) separating said precipitated solid salt obtained in step (b);
(d) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts;
(e) basifying the reaction mixture of step (d) with aqueous base and isolating (R)-enantiomerically enriched 1-indanamine from the obtained mixture; and (f) converting the (R)-enantiomerically enriched 1-indanamine of step (e) to rasagiline or its salts.
According to a preferred embodiment of the invention, the process comprises a step of fractional crystallization of N-benzyl- 1-indanamine
(R,R)-tartrate after step (c). According to another embodiment of the invention, the process of the present invention further comprising the following steps after step (c) and before step (d):
(ci) basifying the mother liqueur of step (c) and isolating (S)-enantiomerically 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).
In accordance with a further aspect of this invention, there is provided a novel compound which is a salt of (R)-enantiomerically enriched
N-benzyl- 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.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides, inter alia, 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. According to a preferred embodiment of the invention, the process is carried out in aqueous medium.
According to another preferred embodiment of the invention, the molar ratio between the racemic N-benzyl- 1-indanamine and (R,R)-tartaric acid is between 1:0.5 and 1 :2. More preferably, the molar ratio is about 1:1.
Preferably, the process for the optical resolution of racemic
N-benzyl- 1-indanamine comprises the following steps:
(a) reacting of 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- 1-indanamine with (R,R)-tartaric acid in solid form;
(c) separating said precipitated 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- 1-indanamine from the obtained mixture. According to a preferred embodiment of the invention, the process further comprising the following steps after step (c) and before step (d):
(ci) basifying the mother liquour of step (c) and isolating (S)-enantiomerically 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).
Racemic N-benzyl- 1-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- 1-indanamine may be racemized in high yield in the presence of strong base or by the method described in Org. 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- 1-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- 1-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 following steps:
(a) reacting of racemic N-benzyl- 1-indanamine with (R,R)-tartaric acid in water; (b) cooling the mixture of step (a) to form the salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (R,R)-tartaric acid in solid form;
(c) separating said precipitated solid salt obtained in step (b);
(d) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts; (e) basifying the reaction mixture of step (d) with aqueous base and isolating (R)-enantiomerically enriched 1-indanamine from the obtained mixture; and (f) converting the (R)-enantiomerically enriched 1-indanamine of step (e) to rasagiline or its salts.
According to another embodiment of the invention, the process of the present invention further comprising steps (ci) to (ciii) mentioned above.
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, (R)-N-benzyl- 1-indanamine (S)-mandelate is not subjected to N-debenzylation without preliminary isolation of (R)-N-benzyl- 1-indanamine from the salt. On the opposite, in the present invention the resolving agent is tartaric acid. This agent is not involved in any undesirable processes under conditions of catalytic hydrogenation. Therefore, there are no obstacles to N-debenzylate the (R)-N-benzyl- 1-indanamine (R,R)-tartrate salt without preliminary isolation of (R)-N-benzyl- 1-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.
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.
Example 2
Preparation of racemic N-benzyl- 1-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.
Example 3
Preparation of (R)-N-benzyl- 1-indanamine (R,R)-tartrate
N-Benzyl-1-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- 1-indanamine (R,R)-tartrate with [α]D2° (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- 1-indanamine (R,R)-tartrate with mp 135-144 °C (dec.) and [O O ° (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
20
N-benzyl- 1-indanamine with [OJD -1-5° (c 5, abs. ethanol), ee ~37.5 %. Example 4
Racemization of (S)-N-benzyl- 1-indanamine
A mixture of (S)-N-benzyl- 1-indanamine (38.9 g, 170 mmol) {[α]D2° -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 [OJD 20 -O.l±O.l0 (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- 1-indanamine (1.5 g, 6.7 mmol) {[α]D2° 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- 1-indanamine (90-95 % yield) with [α]D2° +66±2° (c 2, abs. ethanol).
Example 6
Preparation of (R)- 1-indanamine
A mixture of (R)-N-benzyl- 1-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)-Mndanamine (128.5 g, 72 %) with [α]D2° -16° (c 2.7, methanol) was collected in the fractions of bp 130 - 140 °C.
Example 7
Preparation of (R)- 1-indanamine
A mixture of (R)-N-benzyl- 1-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
90
(120.3 g, 81 %) with [OC]D -16° (c 1.5, methanol) was collected in the fractions ofbp ll8 - 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

CLAEMS:
1. 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- 1 -indanamine (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- 1-indanamine 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 racemic N-benzyl- 1-indanamine and (R,R)-tartaric acid is about 1:1.
5. A process for the optical resolution of racemic N-benzyl- 1-indanamine, 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- 1-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- 1 -indanamine from the obtained mixture.
6. The process according to claim 5 further comprising a step of fractional crystallization of N-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 liquour of step (c) and isolating (S)-enantiomerically 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).
8. A salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (R,R)-tartaric acid.
9. A salt of (R)-enantiomerically enriched N-benzyl- 1-indanamine with (R,R)-tartaric acid for use in the preparation of rasagiline or its salts.
10. A process for the preparation of rasagiline or its salts 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- 1-indanamine with (R,R)-tartaric acid in solid form;
(c) separating said precipitated solid salt obtained in step (b);
(d) hydrogenating under catalytic conditions the solid product of step (c), optionally, in the presence of acids, bases or salts; (e) basifying the reaction mixture of step (d) with aqueous base and isolating (R)-enantiomerically enriched 1-indanamine from the obtained mixture; and (f) converting the (R)-enantiomerically enriched 1-indanamine of step (e) to rasagiline or its salts.
11. The process according to claim 10, further comprising the following steps after step (c) and before step (d):
(ci) basifying the mother liqueur of step (c) and isolating (S)-enantiomerically 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- 1-indanamine (R,R)-tartrate after step (c).
13. Rasagiline or its salts prepared by the process of claim 10.
PCT/IB2002/000542 2001-02-27 2002-02-25 Process for the preparation of rasagiline and its salts WO2002068376A1 (en)

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WO2010070090A1 (en) 2008-12-19 2010-06-24 Ratiopharm Gmbh Solid composition containing the ingredient rasagiline
WO2011003938A1 (en) 2009-07-09 2011-01-13 Ratiopharm Gmbh Salts of rasagiline and pharmaceutical preparations thereof
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WO2015033261A1 (en) 2013-09-03 2015-03-12 Universidade De Évora Process for preparing cyclic chiral amines and alcohols by intramolecular catalytic arylation of boronic acid or ester aldehydes and imine substrates
CN113045456A (en) * 2019-12-26 2021-06-29 上海奥博生物医药技术有限公司 New rasagiline impurity compound and preparation method and application thereof

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CN1990455B (en) * 2005-12-29 2011-06-08 北京德众万全医药科技有限公司 Simple and novel process for preparing indenes derivatives
US7750051B2 (en) 2006-12-14 2010-07-06 Teva Pharmaceutical Industries, Ltd. Crystalline solid rasagiline base
WO2008076348A1 (en) * 2006-12-14 2008-06-26 Teva Pharmaceutical Industries, Ltd. Crystalline solid rasagiline base
US8614252B2 (en) 2006-12-14 2013-12-24 Teva Pharmaceutical Industries Ltd. Crystalline solid rasagiline base
EA016820B1 (en) * 2006-12-14 2012-07-30 Тева Фармасьютикал Индастриз, Лтд. Crystalline solid rasagiline base
AU2009254927B2 (en) * 2008-06-02 2014-03-13 Generics [Uk] Limited A process for the preparation of enantiomerically pure amines
US8569545B2 (en) 2008-06-02 2013-10-29 Generics (Uk) Limited Process for the preparation of enantiomerically pure amines
US8809589B2 (en) 2008-06-02 2014-08-19 Generics [Uk] Limited Process for the preparation of enantiomerically pure amines
JP2011522023A (en) * 2008-06-02 2011-07-28 ジェネリクス・（ユーケー）・リミテッド Process for the preparation of enantiomerically pure amines
CN102123980B (en) * 2008-06-02 2014-05-07 基因里克斯(英国)有限公司 A process for the preparation of enantiomerically pure amines
WO2009147430A1 (en) * 2008-06-02 2009-12-10 Generics [Uk] Limited A process for the preparation of enantiomerically pure amines
US8334409B2 (en) 2008-06-19 2012-12-18 Teva Pharmaceutical Industries, Ltd. Process for purifying rasagiline base
EP2181980A1 (en) 2008-10-28 2010-05-05 Chemo Ibérica, S.A. A process for the preparation of (R)-1-aminoindanes
WO2010070090A1 (en) 2008-12-19 2010-06-24 Ratiopharm Gmbh Solid composition containing the ingredient rasagiline
DE102008064061A1 (en) 2008-12-19 2010-06-24 Ratiopharm Gmbh Solid composition with the active ingredient rasagiline
WO2011003938A1 (en) 2009-07-09 2011-01-13 Ratiopharm Gmbh Salts of rasagiline and pharmaceutical preparations thereof
WO2012116752A1 (en) 2011-03-03 2012-09-07 Synthon Bv Process of resolution of 1-aminoindan
WO2013139387A1 (en) * 2012-03-21 2013-09-26 Synthon Bv Stabilized pharmaceutical compositions comprising rasagiline salts
WO2015033261A1 (en) 2013-09-03 2015-03-12 Universidade De Évora Process for preparing cyclic chiral amines and alcohols by intramolecular catalytic arylation of boronic acid or ester aldehydes and imine substrates
CN113045456A (en) * 2019-12-26 2021-06-29 上海奥博生物医药技术有限公司 New rasagiline impurity compound and preparation method and application thereof

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