雷沙吉兰

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (R)-Rasagiline base pure (30 g) was dissolved in HBr (250 ml) and the solution was heated to reflux for 36 h. After the completion of reaction the mixture was cooled, diluted with water (500 ml) and slowly the solution was basified using aqueous ammonia solution. The mixture was extracted with methyl tertiary butyl ether (MTBE). The separated MTBE layer was evaporated to get a dark brown oil which exhibited 3 spots on TLC, two of which were of the desired compounds i.e., N-2-Propene-1-yl-2-bromo-(R)-aminoindan hydrobromide (Impurity A) and N-2-Propene-1-yl-3-bromo-(R)-aminoindan hydrobromide (Impurity B). The third spot had same Rf as that of the starting material i.e., the unreacted Rasagiline base. The products formed were separated by column chromatography (silica gel) using hexane-ethyl acetate mixture (75:25) as mobile phase to give pure N-2-Propene-1-yl-2-bromo-(R)-aminoindan (15% overall yield) and N-2-Propene-1-yl-3-bromo-(R)-aminoindan (15% overall yield). the solution was heated to reflux for 36 h After the completion of reaction the mixture was cooled The mixture was extracted with methyl tertiary butyl ether (MTBE) The separated MTBE layer was evaporated to get a dark brown oil which The products formed were separated by column chromatography (silica gel)

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Rasagiline base (81 g, 0.47 moles) was dissolved in IPA (810 ml) under stirring and the obtained solution was cooled to 5° C. A solution of methanesulfonic acid (0.49 moles, 47.7 g) in IPA (95 ml) was added dropwise to the above cooled solution. After complete addition, the mixture was stirred for 30 min at 5-10° C. to get the solid which was filtered and dried to get (105 g, 83%) of Rasagiline mesylate. After complete addition the mixture was stirred for 30 min at 5-10° C. to get the solid which was filtered dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: U.S. Pat. No. 5,532,415 discloses process for preparation of R(+)-Rasagiline mesylate which comprises treating a solution of propargyl benzenesulfonate (3) and racemic aminoindan (2) in toluene with aqueous solution of 15% sodium hydroxide to get racemic Rasagiline base (4). The obtained crude racemic Rasagiline is treated with L-tartaric acid in isopropanol (IPA) to get di(R-(+)-N-propargyl-1-aminoindan)-L-tartrate (5) which is recrystallized from 1:1 methanol/isopropanol. The obtained tartrate salt is reacted with methanesulphonic acid in isopropanol at reflux to obtain R(+)-Rasagiline mesylate. The disadvantage of this process is that the scheme consists of low atom efficiency and involves several steps to obtain the final product.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Another process for preparation of Rasagiline hydrochloride as disclosed in EP '492 comprises reaction of R(−)-1-aminoindan (8) with propargyl chloride (6) in presence of potassium carbonate in acetonitrile (ACN) at 60° C. for 16 hours to obtain R(+) Rasagiline base (9) which is then purified by column chromatography. The purified base is then converted to R(+)-Rasagiline hydrochloride followed by recrystallization with isopropanol. The main disadvantage of this process is longer reaction time (16 hours) and low overall yield of about 56%.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: EP436492 discloses process for preparation of R-(+)-Rasagiline hydrochloride which involves reaction of racemic 1-aminoindan (2) with propargyl chloride (6) in presence of potassium carbonate in acetonitrile (ACN) at 60° C. for 16 hours to obtain racemic Rasagiline base (4) which is purified using column chromatography. The ethereal solution of purified racemic base is then treated with HCl gas followed by recrystallization using isopropanol (IPA) to obtain racemic Rasagiline hydrochloride (7). R-(+)-Rasagiline is separated from the obtained racemic Rasagiline base (4) by preparative HPLC chromatography and further converted to its hydrochloride salt.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 60 g rasagiline base were suspended in 885 ml 2-propanol. Then, 32.7 g oxalic acid dissolved in 885 ml 2-propanol were added. The mixture was allowed to stand in a refrigerator overnight, then filtrated and subsequently washed with 100 ml cooled 2-propanol. The residue was dried in a drying cabinet at 45° C. Yield: 87.6 g (93.1% of the theoretical) white crystals; water content (Karl Fischer): about 0.1%; melting point 204° C. (clear, brown melt); TFC: peak at 209.52° C.; [α]D20: +28.9° (2% in ethanol); elemental analysis: C=64.39% (theoretical: 64.36%), H=5.91% (theoretical: 5.79%), N=5.43% (theoretical: 5.36%). were added to stand in a refrigerator overnight filtrated subsequently washed with 100 ml cooled 2-propanol The residue was dried in a drying cabinet at 45° C at 209.52° C.

反应条件: temp:77.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The toluenic phase of step (a) was charged into a 500 mL round-bottomed flask under nitrogen and equipped with mechanical stirring. 110 mL of acetonitrile were then added, followed by the dropwise addition of 32.54 g of methanesulfonic acid in about 20 minutes, maintaining the temperature below 40° C. Precipitation started after the addition of approximately 10% of the total amount of methanesulfonic acid. The thick suspension thus obtained was heated up to 75-80° C. and stirred for 30 min. The suspension was then cooled down to 10-15° C., stirred for at least 1 hour and filtered. The collected solid was washed with 3×20 mL of acetonitrile to yield 74.27 g of yellowish wet product (70.95 g of dry crude, partial yield: 86.20%; 99.32% by HPLC). equipped with mechanical stirring maintaining the temperature below 40° C Precipitation after the addition of approximately 10% of the total amount of methanesulfonic acid The thick suspension thus obtained The suspension was then cooled down to 10-15° C. stirred for at least 1 hour filtered The collected solid was washed with 3×20 mL of acetonitrile

反应条件: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The toluenic phase of step (a) was charged into a 500 mL round-bottomed flask placed in a water/ice bath and equipped with mechanical stirrer. 12.68 mL of methanesulfonic acid were added in about 10-15 minutes, maintaining the temperature below 22° C. After the addition, the reaction mixture was stirred for 1 hour at 20-25° C. The mixture was then filtered, and the filter was washed twice with 10.1 mL of toluene. 55.38 g of wet crude product were obtained (46.40 g of dry crude, partial yield: 97.39%; 73.52% by HPLC). placed in a water/ice bath equipped with mechanical stirrer maintaining the temperature below 22° C After the addition The mixture was then filtered the filter was washed twice with 10.1 mL of toluene

反应条件: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The toluenic phase of step (a) was charged into a 500 mL round-bottomed flask placed in a water/ice bath and equipped with mechanical stirrer. 12.68 mL of methanesulfonic acid were added in about 10-15 minutes, maintaining the temperature below 22° C. After the addition, the reaction mixture was stirred for 1 hour at 20-25° C. The mixture was then filtered, and the filter was washed twice with 10.1 mL of toluene. 55.38 g of wet crude product were obtained (46.40 g of dry crude, partial yield: 97.39%; 73.52% by HPLC). placed in a water/ice bath equipped with mechanical stirrer maintaining the temperature below 22° C After the addition The mixture was then filtered the filter was washed twice with 10.1 mL of toluene

反应条件: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The toluenic phase of step (a) was charged into a 250 mL round-bottomed flask placed in a water/ice bath and equipped with mechanical stirrer. 9.25 mL of methanesulfonic acid were added in about 10-15 minutes, while maintaining the temperature below 22° C. After the addition, the reaction mixture was stirred for an additional 1 hour at 20-25° C. The mixture was then filtered and the filter was washed twice with 10.4 mL of toluene. 41.12 g of wet crude product were obtained (29.64 g of dry crude, partial yield: 85.54%; 79.65% by HPLC). placed in a water/ice bath equipped with mechanical stirrer while maintaining the temperature below 22° C After the addition The mixture was then filtered the filter was washed twice with 10.4 mL of toluene

反应条件: temp:77.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The toluenic phase of step (a) was charged into a 500 mL round-bottomed flask under nitrogen and equipped with mechanical stirring. 110 ml, of acetonitrile were then added, followed by the dropwise addition of 32.54 g of methanesulfonic acid in about 20 minutes, maintaining the temperature below 40° C. Precipitation started after the addition of approximately 10% of the total amount of methanesulfonic acid. The thick suspension thus obtained was heated up to 75-80° C. and stirred for 30 min. The suspension was then cooled down to 10-15° C., stirred for at least 1 hour and filtered. The collected solid was washed with 3×20 mL of acetonitrile to yield 74.27 g of yellowish wet product (70.95 g of dry crude partial yield: 86.20%; 99.32% by HPLC). equipped with mechanical stirring maintaining the temperature below 40° C Precipitation after the addition of approximately 10% of the total amount of methanesulfonic acid The thick suspension thus obtained The suspension was then cooled down to 10-15° C. stirred for at least 1 hour filtered The collected solid was washed with 3×20 mL of acetonitrile

反应条件: temp:77.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The toluenic phase of step (a) was charged into a 500 mL round-bottomed flask under nitrogen and equipped with mechanical stirring. 110 ml, of acetonitrile were then added, followed by the dropwise addition of 32.54 g of methanesulfonic acid in about 20 minutes, maintaining the temperature below 40° C. Precipitation started after the addition of approximately 10% of the total amount of methanesulfonic acid. The thick suspension thus obtained was heated up to 75-80° C. and stirred for 30 min. The suspension was then cooled down to 10-15° C., stirred for at least 1 hour and filtered. The collected solid was washed with 3×20 mL of acetonitrile to yield 74.27 g of yellowish wet product (70.95 g of dry crude partial yield: 86.20%; 99.32% by HPLC). equipped with mechanical stirring maintaining the temperature below 40° C Precipitation after the addition of approximately 10% of the total amount of methanesulfonic acid The thick suspension thus obtained The suspension was then cooled down to 10-15° C. stirred for at least 1 hour filtered The collected solid was washed with 3×20 mL of acetonitrile