161735-79-1

Usage

Uses

Used in Parkinson's Disease Treatment:
Rasagiline mesylate is used as an antiparkinsonian agent for the treatment of idiopathic Parkinson's disease. It acts as a selective irreversible MAO-B inhibitor, which helps in managing the symptoms and progression of the disease.
Used in Alzheimer's Type Dementia Treatment:
Rasagiline is currently in phase II clinical trials at Teva and Eisai for the treatment of Alzheimer's type dementia. Its potential use in this application is due to its MAO-B inhibiting properties, which may help in addressing the cognitive decline associated with dementia.
Used in Monoamine Oxidase B Inhibition:
Rasagiline mesylate is used as a potent and selective irreversible MAO-B inhibitor, which is beneficial in various applications where the inhibition of this enzyme is required. Its prolonged effect may be advantageous in limiting the fluctuating responses characteristic of long-term drug treatments.

Indications

Rasagiline mesylate is a novel, potent, second-generation, selective, irreversible MAO-B inhibitor that blocks the breakdown of dopamine. It is approved for the treatment of PD. Indications for use of once-daily rasagiline are as a monotherapy in early PD and as an adjunct to levodopa in moderate to advanced disease. Rasagiline significantly improves symptoms during initial monotherapy in patients with early PD and as an adjunct treatment to levodopa in moderate-to-advanced patients. Rasagiline is well tolerated up to doses as high as 20 mg/day. Evidence for neuroprotective effect of rasagiline is as follows (Jain 2010c): Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline, which protects mitochondrial viability. Experimental evidence supports rasagiline's neuroprotective efficacy, showing that neuronal survival is related to the anti-apoptotic properties of its propargyl moiety. Aminoindan metabolite of rasagiline has been shown to have neuroprotective properties (Bar-Am et al. 2010).

Biochem/physiol Actions

Rasagiline mesylate is an irreversible inhibitor of monoamine oxidase selective for MAO type B over type A by a factor of fourteen. It has anti-apoptotic and neuroprotectant activity and has been used as a treatment for Parkinson′s disease.

Synthesis

1-Indanone (122) was condensed with benzyl amine to give corresponding enamine which was reduced with sodium borohydride in ethanol to give racemic Nbenzyl- 1-inda-namine (123) in 82% yield. The racemic benzylamine 123 was resolved with L-tartaric acid and recrystallized from boiling water to give optical pure Rbenzylamine 124 as a tartarate salt. The recovered S-isomer 125 can be racemized under basic condition to give back as the starting racemic 123. Compound 124 was hydrogenated and basified to give free amine 126 in 72 % yield which was alkylated with propargyl chloride and K2CO3 in hot acetonitrile to yield free resagiline. Finally resagiline mesilate (XVII) was obtained by treating resagiline with methanesulfonic acid in refluxing IPA.

References

1) Youdim?et al.?(2001),?Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B; Br. J. Pharmacol.,?132?500 2) Cereda?et al.?(2017),?Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case-control study; J. Neurol.,?264?1254 3) Cronin and Grealy (2017),?Neuroprotective and Neuro-restorative Effects of Minocycline and Rasagiline in Zebrafish 6-Hydroxydopamine Model of Parkinson’s Disease; Neuroscience,?367?34 4) Kang?et al.?(2017),?TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease; Proc. Natl. Acad. Sci. USA,?114?10773 5) Ledreux?et al.?(2016),?BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson’s disease; Brain Res.,?1631?34

InChI:InChI=1/C12H13N.CH4O3S/c1-2-9-13-12-8-7-10-5-3-4-6-11(10)12;1-5(2,3)4/h1,3-6,12-13H,7-9H2;1H3,(H,2,3,4)/t12-;/m1./s1

Synthetic route

methanesulfonic acid (75-75-2) + rasagiline (136236-51-6) → rasagiline mesylate (161735-79-1)

Conditions	Yield
In isopropyl alcohol for 1h; Reflux;	98%
In toluene; acetonitrile at 40 - 80℃; Product distribution / selectivity;	86.2%
In isopropyl alcohol at 5 - 10℃; for 0.5h;	83%

methanesulfonic acid (75-75-2) + (1R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine hemihydrate → rasagiline mesylate (161735-79-1)

Conditions	Yield
Stage #1: (1R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine hemihydrate With potassium carbonate In water pH=Ca. 10; Large scale; Stage #2: methanesulfonic acid In isopropyl alcohol at 20℃; for 1.5h; Large scale;	92.6%

methanesulfonic acid (75-75-2) + (1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine L-(+)-tartrate → rasagiline mesylate (161735-79-1)

Conditions	Yield
Stage #1: (1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine L-(+)-tartrate With sodium hydrogencarbonate In water; ethyl acetate at 20 - 25℃; Inert atmosphere; Stage #2: methanesulfonic acid In isopropyl alcohol Reflux;	89%

methanesulfonic acid (75-75-2) + rasagiline tartrate → rasagiline mesylate (161735-79-1)

Conditions	Yield
In isopropyl alcohol at 5℃; for 1.5h; Reflux;	83%

methanesulfonic acid (75-75-2) + rasagiline tartrate → rasagiline mesylate (161735-79-1)

Conditions	Yield
In isopropyl alcohol at 5 - 10℃; for 0.75h;	83%

methanesulfonic acid (75-75-2) + N-(2,3 dibromopropyl)-1-aminoindan (1166392-46-6) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Stage #1: N-(2,3 dibromopropyl)-1-aminoindan With potassium hydroxide In denaturated industrial spirit; water at 80 - 90℃; for 5h; Stage #2: methanesulfonic acid In isopropyl alcohol at 25 - 30℃;

methanesulfonic acid (75-75-2) + (R-(+)-N-propargyl-1-aminoindan)L-tartarate → rasagiline mesylate (161735-79-1)

Conditions	Yield
In acetone for 0.75h; Product distribution / selectivity; Reflux;	n/a

2,3-dihydro-1H-inden-1-amine (34698-41-4) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / 24 h / 55 °C 2.1: isopropyl alcohol / 1.5 h / 25 - 30 °C / Reflux 3.1: ammonia / water / pH ~ 8.5 - 9 3.2: 2 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate; N,N-dimethyl-formamide; sodium hydroxide / 7 h / 40 - 70 °C 2: 0.75 h / 25 - 65 °C 3: sodium hydroxide / water / 20 °C 4: acetone / 1 h / 25 - 35 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate; N,N-dimethyl-formamide; sodium hydroxide / 7 h / 40 - 70 °C 2.1: 0.75 h / 25 - 65 °C 3.1: sodium hydroxide / water / 20 °C 4.1: hydrogen bromide / 0.5 h / 25 - 65 °C 5.1: sodium hydroxide / ethyl acetate / 4 h / 65 °C 5.2: 0.5 h / 40 °C View Scheme
Multi-step reaction with 4 steps 1: Candida antarctica lipase B; Pd/AlO(OH); potassium carbonate / toluene / 12 h / 50 °C / Resolution of racemate; Inert atmosphere; Schlenk technique; Enzymatic reaction 2: triethanolamine; sodium hydroxide / water / 6.25 h / 80 °C / Reflux 3: potassium carbonate / acetonitrile / 12 h / 30 °C / Reflux 4: isopropyl alcohol / 0.5 h / 5 - 10 °C View Scheme
Multi-step reaction with 6 steps 1: ethanol; tert-butyl methyl ether / 20 °C 2: ethanol / 2.32 h / 79 °C 3: sodium hydroxide / ethyl acetate / 0.5 h / 20 °C 4: hydrogenchloride / isopropyl alcohol / 0.5 h / 5 - 20 °C / Inert atmosphere 5: sodium hydroxide / toluene / 29 h / 30 °C 6: isopropyl alcohol / 1 h / 55 - 80 °C View Scheme

methanesulfonic acid (75-75-2) + (1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine L-(+)-tartrate (1201685-18-8) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Stage #1: (1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine L-(+)-tartrate With ammonia In water pH=~ 8.5 - 9; Stage #2: methanesulfonic acid In acetone at 25 - 30℃; for 2h; Product distribution / selectivity;

inden-1-one (83-33-0) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: ethanol / 8 h / 25 - 30 °C 2.1: ethanol; sodium tetrahydroborate / 8 h / 25 - 30 °C 3.1: isopropyl alcohol / 1.5 h / 25 - 30 °C / Reflux 4.1: ammonia / water / pH ~ 8.5 - 9 4.2: 2 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid / tert-butyl methyl ether / 8 h 1.2: 1 h / -70 - -30 °C 2.1: diisobutylaluminium hydride / toluene; hexane / 1 h / -70 - -30 °C 2.2: 1 h / 20 °C 3.1: tert-butyl methyl ether / 21 h / 10 °C / Heating 4.1: sodium hydroxide 5.1: isopropyl alcohol / 16 h / 20 - 75 °C View Scheme
Multi-step reaction with 6 steps 1: hydroxylamine hydrochloride; sodium hydroxide / water; methanol / 70 - 75 °C 2: hydrogen; ammonia / Raney nickel / methanol / 10 - 42 °C / Autoclave 3: potassium carbonate; N,N-dimethyl-formamide; sodium hydroxide / 7 h / 40 - 70 °C 4: 0.75 h / 25 - 65 °C 5: sodium hydroxide / water / 20 °C 6: acetone / 1 h / 25 - 35 °C View Scheme

C21H33NO4Ti → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ethanol; sodium tetrahydroborate / 8 h / 25 - 30 °C 2.1: isopropyl alcohol / 1.5 h / 25 - 30 °C / Reflux 3.1: ammonia / water / pH ~ 8.5 - 9 3.2: 2 h / 25 - 30 °C View Scheme

rasagiline (136236-51-6) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogen bromide / 0.5 h / 25 - 65 °C 2.1: sodium hydroxide / ethyl acetate / 4 h / 65 °C 2.2: 0.5 h / 40 °C View Scheme

N-propargyl-1-aminoindan (1875-50-9) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tert-butyl methyl ether / 21 h / 10 °C / Heating 2: sodium hydroxide 3: isopropyl alcohol / 16 h / 20 - 75 °C View Scheme
Multi-step reaction with 3 steps 1: 0.75 h / 25 - 65 °C 2: sodium hydroxide / water / 20 °C 3: acetone / 1 h / 25 - 35 °C View Scheme
Multi-step reaction with 4 steps 1.1: 0.75 h / 25 - 65 °C 2.1: sodium hydroxide / water / 20 °C 3.1: hydrogen bromide / 0.5 h / 25 - 65 °C 4.1: sodium hydroxide / ethyl acetate / 4 h / 65 °C 4.2: 0.5 h / 40 °C View Scheme

N-(2,3-dihydroinden-1-ylidene)prop-2-yn-1-amine (1227784-59-9) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: diisobutylaluminium hydride / toluene; hexane / 1 h / -70 - -30 °C 1.2: 1 h / 20 °C 2.1: tert-butyl methyl ether / 21 h / 10 °C / Heating 3.1: sodium hydroxide 4.1: isopropyl alcohol / 16 h / 20 - 75 °C View Scheme

R-(+)-N-propargyl-1-aminoindane L-(+)-mandelate (1309125-23-2) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide 2: isopropyl alcohol / 16 h / 20 - 75 °C View Scheme

(R)-2,3-dihydro-1H-inden-1-amine hydrochloride → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / water / 0.25 h / 15 - 20 °C 1.2: 2.75 h / 15 - 20 °C 2.1: isopropyl alcohol / 0.5 h / 5 - 10 °C View Scheme
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0.58 h / 20 °C / Ice bath 2.1: caesium carbonate / acetonitrile / 0.17 h / 30 - 35 °C 2.2: 4 h / 30 - 35 °C 3.1: potassium hydroxide / water; methanol / 30 - 35 °C 4.1: isopropyl alcohol / 20 - 60 °C 4.2: 0.42 h / 20 - 60 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / water / 0.25 h / 15 - 20 °C 1.2: 2.75 h / 15 - 20 °C 2.1: isopropyl alcohol / 0.5 h / 5 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / toluene / 29 h / 30 °C 2: isopropyl alcohol / 1 h / 55 - 80 °C View Scheme

N-trifluoroacetyl-(R)-1-aminoindan (155666-94-7) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: caesium carbonate / acetonitrile / 0.17 h / 30 - 35 °C 1.2: 4 h / 30 - 35 °C 2.1: potassium hydroxide / water; methanol / 30 - 35 °C 3.1: isopropyl alcohol / 20 - 60 °C 3.2: 0.42 h / 20 - 60 °C View Scheme
Multi-step reaction with 3 steps 1: caesium carbonate / acetonitrile; toluene / 30 - 35 °C 2: potassium hydroxide; water / methanol / 0.5 h / 30 - 35 °C 3: isopropyl alcohol / 50 - 60 °C View Scheme

methanesulfonic acid (75-75-2) + (1R)-2,3-dihydro-N-2-propynyl-1H-indane-1-amine hydrobromide (694436-33-4) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Stage #1: (1R)-2,3-dihydro-N-2-propynyl-1H-indane-1-amine hydrobromide With sodium hydroxide In ethyl acetate at 65℃; for 4h; Stage #2: methanesulfonic acid In ethyl acetate at 40℃; for 0.5h;

indan-1-one oxime (68253-35-0, 100485-57-2, 3349-60-8) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogen; ammonia / Raney nickel / methanol / 10 - 42 °C / Autoclave 2: potassium carbonate; N,N-dimethyl-formamide; sodium hydroxide / 7 h / 40 - 70 °C 3: 0.75 h / 25 - 65 °C 4: sodium hydroxide / water / 20 °C 5: acetone / 1 h / 25 - 35 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydrogen; ammonia / Raney nickel / methanol / 10 - 42 °C / Autoclave 2.1: potassium carbonate; N,N-dimethyl-formamide; sodium hydroxide / 7 h / 40 - 70 °C 3.1: 0.75 h / 25 - 65 °C 4.1: sodium hydroxide / water / 20 °C 5.1: hydrogen bromide / 0.5 h / 25 - 65 °C 6.1: sodium hydroxide / ethyl acetate / 4 h / 65 °C 6.2: 0.5 h / 40 °C View Scheme
Multi-step reaction with 5 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 4 h / 70 °C 2: Candida antarctica lipase B; Pd/AlO(OH); potassium carbonate / toluene / 12 h / 50 °C / Resolution of racemate; Inert atmosphere; Schlenk technique; Enzymatic reaction 3: triethanolamine; sodium hydroxide / water / 6.25 h / 80 °C / Reflux 4: potassium carbonate / acetonitrile / 12 h / 30 °C / Reflux 5: isopropyl alcohol / 0.5 h / 5 - 10 °C View Scheme
Multi-step reaction with 7 steps 1: ammonia; hydrogen / methanol / 20 h / 42 °C / 2625.26 Torr 2: ethanol; tert-butyl methyl ether / 20 °C 3: ethanol / 2.32 h / 79 °C 4: sodium hydroxide / ethyl acetate / 0.5 h / 20 °C 5: hydrogenchloride / isopropyl alcohol / 0.5 h / 5 - 20 °C / Inert atmosphere 6: sodium hydroxide / toluene / 29 h / 30 °C 7: isopropyl alcohol / 1 h / 55 - 80 °C View Scheme

di-(R-(+)-N-propargyl-1-aminoindan) L-tartrate → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 20 °C 2.1: hydrogen bromide / 0.5 h / 25 - 65 °C 3.1: sodium hydroxide / ethyl acetate / 4 h / 65 °C 3.2: 0.5 h / 40 °C View Scheme

N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-methoxyacetamide → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethanolamine; sodium hydroxide / water / 6.25 h / 80 °C / Reflux 2: potassium carbonate / acetonitrile / 12 h / 30 °C / Reflux 3: isopropyl alcohol / 0.5 h / 5 - 10 °C View Scheme

(S)-1-Aminoindane (10277-74-4, 34698-41-4, 61341-86-4, 61949-83-5) → rasagiline mesylate (161735-79-1)

Conditions

Yield

Multi-step reaction with 5 steps 1: Pd/AlO(OH) / toluene / 6 h / 70 °C / Inert atmosphere; Schlenk technique 2: Candida antarctica lipase B; Pd/AlO(OH); potassium carbonate / toluene / 12 h / 50 °C / Resolution of racemate; Inert atmosphere; Schlenk technique; Enzymatic reaction 3: triethanolamine; sodium hydroxide / water / 6.25 h / 80 °C / Reflux 4: potassium carbonate / acetonitrile / 12 h / 30 °C / Reflux 5: isopropyl alcohol / 0.5 h / 5 - 10 °C View Scheme

3-Phenylpropionic acid (501-52-0) → rasagiline mesylate (161735-79-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: polyphosphoric acid / 0.5 h / 90 °C 2: hydroxylamine hydrochloride / ethanol; water / 0.75 h / Reflux 3: palladium 10% on activated carbon; hydrogen / ethanol / 4 h / 70 °C 4: Candida antarctica lipase B; Pd/AlO(OH); potassium carbonate / toluene / 12 h / 50 °C / Resolution of racemate; Inert atmosphere; Schlenk technique; Enzymatic reaction 5: triethanolamine; sodium hydroxide / water / 6.25 h / 80 °C / Reflux 6: potassium carbonate / acetonitrile / 12 h / 30 °C / Reflux 7: isopropyl alcohol / 0.5 h / 5 - 10 °C View Scheme

2,3-dihydro-1H-inden-1-yl-acetate (26452-98-2) → rasagiline mesylate (161735-79-1)

Conditions

Yield

Multi-step reaction with 5 steps 1: Candida rugosa lipase / tetrahydrofuran; aq. phosphate buffer / 24 h / 30 °C / pH 7 / Resolution of racemate; Enzymatic reaction 2: diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 22 h / 0 - 20 °C / Inert atmosphere 3: triphenylphosphine; potassium hydroxide; water / tetrahydrofuran / 24 h / 20 °C 4: potassium carbonate / acetonitrile / 16 h / 60 °C 5: isopropyl alcohol / 1 h / Reflux View Scheme

1-Indanol (6351-10-6) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: Thermomyces lanuginosus lipase / hexane / 0.25 h / 35 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 2: diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 22 h / 0 - 20 °C / Inert atmosphere 3: triphenylphosphine; potassium hydroxide; water / tetrahydrofuran / 24 h / 20 °C 4: potassium carbonate / acetonitrile / 16 h / 60 °C 5: isopropyl alcohol / 1 h / Reflux View Scheme
Multi-step reaction with 5 steps 1: pseudomonas fluorescens lipase / toluene / 6 h / 30 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 2: diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 22 h / 0 - 20 °C / Inert atmosphere 3: triphenylphosphine; potassium hydroxide; water / tetrahydrofuran / 24 h / 20 °C 4: potassium carbonate / acetonitrile / 16 h / 60 °C 5: isopropyl alcohol / 1 h / Reflux View Scheme
Multi-step reaction with 6 steps 1: dmap / dichloromethane / 4 h / 20 °C 2: Candida rugosa lipase / tetrahydrofuran; aq. phosphate buffer / 24 h / 30 °C / pH 7 / Resolution of racemate; Enzymatic reaction 3: diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 22 h / 0 - 20 °C / Inert atmosphere 4: triphenylphosphine; potassium hydroxide; water / tetrahydrofuran / 24 h / 20 °C 5: potassium carbonate / acetonitrile / 16 h / 60 °C 6: isopropyl alcohol / 1 h / Reflux View Scheme

(S)-indanol (25501-32-0) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 22 h / 0 - 20 °C / Inert atmosphere 2: triphenylphosphine; potassium hydroxide; water / tetrahydrofuran / 24 h / 20 °C 3: potassium carbonate / acetonitrile / 16 h / 60 °C 4: isopropyl alcohol / 1 h / Reflux View Scheme

(R)-(+)-1-azidoindan → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: triphenylphosphine; potassium hydroxide; water / tetrahydrofuran / 24 h / 20 °C 2: potassium carbonate / acetonitrile / 16 h / 60 °C 3: isopropyl alcohol / 1 h / Reflux View Scheme

(R)-1-Aminoindane (10277-74-4) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 16 h / 60 °C 2: isopropyl alcohol / 1 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / isopropyl alcohol / 0.5 h / 5 - 20 °C / Inert atmosphere 2: sodium hydroxide / toluene / 29 h / 30 °C 3: isopropyl alcohol / 1 h / 55 - 80 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 16 h / 60 °C 2: isopropyl alcohol / 1 h / 70 - 75 °C View Scheme
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 15 - 20 °C / Inert atmosphere 2: triphenylsilyl radical; 2-Chlorobenzeneboronic acid / toluene / 24 h / 10 - 15 °C / Inert atmosphere 3: isopropyl alcohol / 1 h / 70 - 75 °C View Scheme

(R)-1-aminoindan (S)-N-acetyl-L-glutaminate (2:1) → rasagiline mesylate (161735-79-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / ethyl acetate / 0.5 h / 20 °C 2: hydrogenchloride / isopropyl alcohol / 0.5 h / 5 - 20 °C / Inert atmosphere 3: sodium hydroxide / toluene / 29 h / 30 °C 4: isopropyl alcohol / 1 h / 55 - 80 °C View Scheme

rasagiline mesylate (161735-79-1) → rasagiline (136236-51-6)

Conditions	Yield
With sodium hydroxide In water at 3 - 5℃; for 1h; pH=7.5 - 11; Product distribution / selectivity;	91.6%
With sodium hydroxide In water at 3 - 5℃; pH=11;	91.6%
With sodium hydroxide In water; toluene pH=~ 14;
With sodium hydroxide In water; toluene pH=14;

(R-(+)-N-propargyl-1-aminoindan)L-tartarate + rasagiline mesylate (161735-79-1) → rasagiline (136236-51-6)

Conditions	Yield
With sodium hydroxide In water; toluene at 40 - 50℃; pH=14; Product distribution / selectivity;

Upstream product

• 75-75-2 methanesulfonic acid 
• 136236-51-6 rasagiline 
• 1166392-46-6 N-(2,3 dibromopropyl)-1-aminoindan 
• 1875-50-9 N-propargyl-1-aminoindan 
• 1227784-59-9 N-(2,3-dihydroinden-1-ylidene)prop-2-yn-1-amine 
• 1309125-23-2 R-(+)-N-propargyl-1-aminoindane L-(+)-mandelate 
• 10305-73-4 (R)-2,3-dihydro-1H-inden-1-amine hydrochloride 
• 694436-33-4 (1R)-2,3-dihydro-N-2-propynyl-1H-indane-1-amine hydrobromide 
• 68253-35-0 indan-1-one oxime 
• 10277-74-4 (S)-1-Aminoindane 
• 501-52-0 3-Phenylpropionic acid 
• 26452-98-2 2,3-dihydro-1H-inden-1-yl-acetate 
• 6351-10-6 1-Indanol 
• 25501-32-0 (S)-indanol 

Downstream Products

• 136236-51-6 rasagiline 

Relevant academic research and scientific papers

Improved preparation method of rasagiline racemic intermediate

The invention discloses an improved preparation method of a rasagiline racemic intermediate, belongs to the technical field of medicinal chemistry, and particularly relates to an improved method for preparing an N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine racemic body. According to the invention, the N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine racemic body is prepared by using 1-indanone and propargylamine as raw materials through a one-pot method in the presence of a dehydrating agent; and the method is simple to operate, high in yield and good in purity, and establishes a good foundationfor subsequent preparation of rasagiline mesylate.

Preparation method of rasagiline mesylate and intermediate thereof

The invention discloses a preparation method of rasagiline mesylate and an intermediate thereof. The invention provides the preparation method of rasagiline mesylate I. The preparation method comprises the following steps: S1, in an organic solvent, in the presence of a reducer and a catalyst, carrying out a reduction reaction on a rasagiline mesylate intermediate II and the reducer to obtain a rasagiline mesylate intermediate III; and S2, in an organic solvent, carrying out a salt forming reaction on the rasagiline mesylate intermediate III obtained in the S1 and methanesulfonic acid to obtain rasagiline mesylate I. The preparation method does not employ an amino alkylation reaction which is relatively more in side reaction, and the prepared rasagiline mesylate I is high in purity, reaches the demand on bulk pharmaceutical chemicals, the purity is greater than 99.5%, the maximum single impurities are smaller than 0.10%, the yield is high, the production cost is low, and the method issuitable for industrial production. The formula is as shown in the description.

PROCESS FOR THE PREPARATION OF ENATIOMERICALLY PURE 1-AMINOINDAN

The present invention relates to a process for the preparation of optically pure ( R) -1-aminoindan by a diastereomeric resolution of 1-aminoindan using N-acetyl-L-glutamic acid as a resolving agent. In another aspect, the invention relates to diastereomeric salts of (R) -1-aminoindan with N-acetyl-L-glutamic acid, and their use in the process for the preparation of rasagiline.

Chemoenzymatic synthesis of rasagiline mesylate using lipases

A straightforward chemoenzymatic synthesis of rasagiline mesylate has been developed. The key steps for the introduction of chirality involved kinetic enzymatic resolution with lipases via acetylation of racindanol and an inversion configuration Mitsunobu reaction of the produced (S)-indanol. Immobilized lipase from Thermomyces lanuginosus proved to be a robust biocatalyst in the kinetic resolution, leading to (S)-indanol with high selectivity (e.e. > 99%, E > 200) in just 15 min, at 35°C, in hexane, being reused for ten-times without significant loss of the activity and selectivity.

A novel synthesis of rasagiline via a chemoenzymatic dynamic kinetic resolution

A novel synthetic route for preparing rasagiline mesylate is presented using a dynamic kinetic resolution (DKR) as the key step, catalyzed by Candida antarctica lipase B (CALB) and a Pd nanocatalyst. The chiral intermediate (R)-2,3-dihydro-1-indanamine was obtained through the DKR of the racemic aminoindan rac-1 in high yield (>90%) and excellent enantioselectivity (>99% ee). The process could be conducted on a 73 g scale at 200 g/L. Rasagiline mesylate was synthesized in 25% overall yield and excellent enantioselectivity (99.9% ee) over 7 steps.

NEW METHOD FOR THE SYNTHESIS OF RASAGILINE

We have developed a new method for the synthesis of Rasagiline (Formula 1) based on the alkylation of trifluoroacetyl protected aminoindan. This protection enabled us to carry out an alkylation of aminoindan with a high yield and purity under very mild conditions with a wide range of reaction conditions and reagent selection. Considering the ease, purity and high yields of introducing and removal of the trifluoroacetyl group, this approach is a highly practical and economical way for the synthesis of rasagiline or its pharmaceutically acceptable salts.

Process for preparation of Rasagiline and salts thereof

The present invention relates to an improved process for the preparation of Rasagiline or pharmaceutically acceptable salts thereof. The present invention also relates to Rasagiline salts, polymorphs thereof and process for preparation thereof.

A PROCESS FOR THE PREPARATION OF N-PROPRAGYL 1-AMINO INDANE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention is directed to a process for the preparation of N-propargyl 1 -amino indane and pharmaceutically acceptable salts thereof by a process comprising: a) providing a reaction mixture comprising N-propargyl-1 -amino indane and/or a salt thereof, b) purifying N-propargyl-1 -amino indane free base exclusively by selective pH adjustment and selective extraction, c) optionally isolating N-propargyl- 1 -amino indane free base or converting insitu to its pharmaceutically acceptable salt thereof.

A NEW METHOD FOR THE SYNTHESIS OF RASAGILINE

We have developed a new method for the synthesis of Rasagiline (Formula 1) based on the alkylation of trifluoroacetyl protected aminoindan. This protection enabled us to carry out an alkylation of aminoindan with a high yield and purity under very mild conditions with a wide range of reaction conditions and reagent selection. Considering the ease, purity and high yields of introducing and removal of the trifluoroacetyl group, this approach is a highly practical and economical way for the synthesis of rasagiline or its pharmaceutically acceptable salts.

RASAGILINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

The present invention relates to Rasagiline acid addition salts having a particle size D(90) greater than 250 microns and D(50) greater than 100 microns, with the proviso that acid addition salt is not mesylate. The invention also discloses a process for the preparation of such Rasagiline acid addition salts.