136236-51-6

Usage

Uses

Used in Pharmaceutical Industry:
Rasagiline is used as a 5HT4 receptor agonist and peristaltic stimulant for the treatment of Parkinson's disease. It acts as an adjunct therapy to treat fluctuations in motor symptoms, reducing the time spent in the "off" state and increasing the "on" time.
Used in Parkinson's Disease Treatment:
Rasagiline is used as a selective, irreversible monoamine oxidase-B inhibitor to increase the availability of dopamine at striatal receptors, providing relief from motor symptoms associated with Parkinson's disease.
Brand Name:
Azilect (Teva)

Originator

Teva/Eisai/Lundbeck (Israel)

Characteristics

Rasagiline, [N-propargyl-1R(+)aminoindan] is a unique, selective, and potent secondgeneration mitochondrial monoamine oxidase B inhibitor with distinctive neuroprotective as well as therapeutic properties for the treatment of PD.

Indications

Rasagiline has a role in the treatment of PD by virtue of its proven ability to reduce the signs of PD in both the “on” and “off” states, and to improve global function. It appears to be of value in early stages of PD as well as after the appearance of clinical fluctuations in response to LD. Rasagiline also has a promising but not fully explored potential to halt or slow down the progression of PD, as well as other clinical conditions. The accumulating evidence of rasagiline’s neuroprotective effects in animal and cellular models is both intriguing and exciting. Further careful scientific basic and clinical studies and clinical experience are needed to establish the full therapeutic benefits of rasagiline for the treatment of PD.

Mechanism of action

Rasagiline has many neuroprotective properties in animal and cell culture models of PD as well as a variety of other conditions that are too numerous to delineate completely, so only some of these studies are mentioned here. Some studies suggest that the neuroprotective effects of rasagiline are potentially separate and unrelated to its therapeutic effects.For example, the S-enantiomer of rasagiline lacks the MAOB inhibitory and the antidepressant effects of rasagiline but shares with rasagiline its neuroprotective effects and its cholinesterase inhibitory effects.This suggests that the neuroprotective effects of rasagiline are independent of its antidepressant and MAOB inhibitory effects. Rasagiline protects dopaminergic SHSY5Y cells in culture by inhibiting mitochondrial permability transition, an apoptosis inducing effect, of an endogenous neurotoxin (N-methyl(R) salsolinol).In the same cell model, rasagiline also enhances the expression of the Bcl-2 gene family which have antiapoptotic effects.Finally, rasagiline prevents the apoptosis and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by N-methyl (R) salsonilol in human dopaminergic SH-SY5Y cell cultures.Since the SH-SY5Y cell system does not contain MAO, these protective effects must have other mechanisms. Rasagiline also is protective in vivo against MPTP (mice) and 6OHDA (rats) (see Reference 100). In primate models of PD, rasagiline led to a return toward normal of cognitive and motor function, even in the absence of LD. In neuronal cell models (SH-SY5Y neuroblastoma cells and neuronally differentiated PC12 cells), rasagiline increases SOD activity and Bcl-2 expression, and it inhibits activation of capsase 3, prevents DNA laddering, inhibits toxin induced fall in mitochondrial membrane potential, prevents toxin induced apoptosis, and protects against cell death due to ischemia and glucose deprivation.Rasagiline also has protective effects against stroke occurrence and promotes survival in spontaneously hypertensive rats.

Pharmacokinetics

Rasagiline, or TV3326, or [N-propargyl-1R(+)ami-noindan], is a selective and highly potent second-generation mitochondrial monoamine oxidase B inhibitor.As opposed to selegiline, rasagiline has quite a different metabolite profile. Selegiline’s major metabolites are amphetamine and methamphetamine, while rasagiline’s primary metabolite is aminoindan. While amphetamine and methamphetamine are potently addictive substances, they may promote alertness. Aminoindan has beneficial effects of its own and has no known adverse side effects.In man, 1-mg daily dosages of rasagiline inhibit platelet MAO-B nearly completely.Rasagiline has both therapeutic and protective properties.

Clinical Use

Rasagiline [R(+)-N-propargyl-1-aminoindan] mesylate (Azilect?) was approved by the FDAin May of 2006 as monotherapy in early disease and as an adjunct to levodopa in more advanced disease. The recommended doses are 1 mg once a day in early disease and an initial dose of 0.5 mg once a day in advanced disease that can be increased to 1 mg once a day if needed. It produces selective irreversible MAO-B inhibition. Platelet MAO-B inhibition is dose-dependent; one hour after ingestion, platelet MAOB inhibition is 35% with 1 mg rasagiline and 99% with 10 mg rasagiline. By day 6, rasagiline 2 mg/day inhibits over 99% of platelet MAO-B. After discontinuing rasagiline, it takes approximately two weeks for MAO-B activity to return to baseline values. The area under the curve (AUC) and maximum concentration (Cmax) increase linearly with rasagiline dosage. The plasma half-lives of rasagiline and its active metabolite 1(R)-aminoindan are 3.5 hours and 11 hours, respectively. As rasagiline irreversibly inhibits MAO-B, the serum (pharmacokinetic) half-life does not correlate with its functional (pharmacodynamic) half-life. Rasagiline up to 20 mg/day was well tolerated in healthy male volunteers. Dry mouth, headache, nausea, thirst, and abdominal discomfort were the most common adverse effects but tended to be mild. There were no significant effects on vital signs, lab values, physical exam, or EKG.

Drug interactions

Potentially hazardous interactions with other drugs Analgesics: avoid with dextromethorphan; avoid with pethidine (risk of serious adverse reactions) - allow at least 14 days before starting pethidine. Antidepressants: avoid with other MAOIs (can lead to hypertensive crisis) - allow at least 14 days before starting a MAOI; avoid with fluoxetine and fluvoxamine; allow 5 weeks between stopping fluoxetine and starting rasagiline; allow 14 days between stopping rasagiline and starting fluoxetine or fluvoxamine; increased CNS toxicity with SSRIs, tricyclics and vortioxetine. Sympathomimetics: concomitant use is not recommended.

Metabolism

Rasagiline is extensively metabolised in the liver by N-dealkylation and hydroxylation, via the cytochrome P450 isoenzyme CYP1A2, and conjugation. 1-Aminoindan is a major metabolite and is stated to be active although it is not a monoamine oxidase B inhibitor. The metabolites are excreted mainly in the urine and partly in the faeces.

InChI:InChI=1/C12H11N/c1-2-9-13-12-8-7-10-5-3-4-6-11(10)12/h1,3-8,12-13H,9H2/t12-/m1/s1

Synthetic route

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

Conditions	Yield
With sodium hydroxide In water; toluene at 45℃; for 0.25h; pH=13 - 14;	96%
With sodium hydroxide In water; toluene at 45℃; for 0.25h; Product distribution / selectivity;	92%
With sodium hydroxide In water pH=11.98; Product distribution / selectivity;	n/a

(R)-tert-butyl 2,3-dihydro-1H-inden-1-yl(prop-2-ynyl)carbamate (1224439-21-7) → rasagiline (136236-51-6)

Conditions	Yield
Stage #1: (R)-tert-butyl 2,3-dihydro-1H-inden-1-yl(prop-2-ynyl)carbamate With hydrogenchloride; water In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; water Inert atmosphere;	95%

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-aminoindane L-(+)-mandelate (1309125-23-2) → rasagiline (136236-51-6)

Conditions	Yield
With sodium hydroxide	90%

(R)-N-(2-chloroallyl)-2,3-dihydro-1H-inden-1-amine (1175018-73-1) → rasagiline (136236-51-6)

Conditions	Yield
With sodium t-butanolate In ISOPROPYLAMIDE at 0 - 5℃; for 2.16667h; Product distribution / selectivity; Inert atmosphere;	82%

(R)-1-Aminoindane (10277-74-4) + 2-propynyl chloride (624-65-7) → rasagiline (136236-51-6)

Conditions	Yield
With potassium carbonate In acetonitrile at 60℃; for 16h;	79%
With potassium carbonate In acetonitrile at 60℃; for 16h;

propargyl benzenesulfonate (6165-75-9) + (R)-1-Aminoindane (10277-74-4) → rasagiline (136236-51-6)

Conditions	Yield
With sodium hydroxide In water; toluene at 30 - 50℃; Product distribution / selectivity;	74.56%

propargyl benzenesulfonate (6165-75-9) + (R)-2,3-dihydro-1H-inden-1-amine hydrochloride → rasagiline (136236-51-6)

Conditions	Yield
With sodium hydroxide In toluene at 30℃; for 29h;	65.8%
With sodium hydroxide In toluene at 30℃; for 29h;	65.8%
Stage #1: (R)-2,3-dihydro-1H-inden-1-amine hydrochloride With tetrabutylammomium bromide; sodium hydroxide In water at 15 - 20℃; for 0.25h; Stage #2: propargyl benzenesulfonate In water at 15 - 20℃; for 2.75h;
Stage #1: (R)-2,3-dihydro-1H-inden-1-amine hydrochloride With tetrabutylammomium bromide; sodium hydroxide In water at 15 - 20℃; for 0.25h; Stage #2: propargyl benzenesulfonate In water at 15 - 20℃; for 2.75h;	81.0 g

(R)-N-indan-1-yl-4-nitro-N-prop-2-ynyl-benzenesulfonamide (915797-28-3) → rasagiline (136236-51-6)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol	64%

(R)-1-Aminoindane (10277-74-4) + propargyl bromide (106-96-7) → rasagiline (136236-51-6)

Conditions	Yield
With potassium carbonate In acetonitrile at 30℃; for 12h; Reflux;	59.7%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 0.166667h; Flow reactor;	58%
With triethylamine In tetrahydrofuran at 50℃;

INDANE (496-11-7) → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: Rh2[(S)-(adamantan-1-yl)(tetrachlorophthalimido)CHCOO]4; PhI(OAc)2 / various solvent(s) / 3 h / 23 °C 2: 75 percent / K2CO3 3: 64 percent / DBU; HSC2H4OH View Scheme

(R)-N-indan-1-yl-4-nitrobenzenesulfonamide (217640-41-0) → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / K2CO3 2: 64 percent / DBU; HSC2H4OH View Scheme

C10H12O3S + Propargylamine (2450-71-7) → rasagiline (136236-51-6) + N-Propargyl-1(S)-aminoindan

Conditions	Yield
In dichloromethane at -29 - 20℃;	A n/a B n/a

di-(R-(+)-N-propargyl-1-aminoindan) L-tartrate → rasagiline (136236-51-6)

Conditions	Yield
With sodium hydroxide In water; toluene
With sodium hydroxide In water at 20℃;

(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;

R-(-)-N-(2,3 dibromopropyl)-1-aminoindan (1166392-44-4) → rasagiline (136236-51-6)

Conditions	Yield
With potassium hydroxide In denaturated industrial spirit; water at 80 - 90℃; for 5h;

propargyl p-toluenesulfonate (6165-76-0) + (R)-1-Aminoindane (10277-74-4) → rasagiline (136236-51-6)

Conditions	Yield
Stage #1: (R)-1-Aminoindane With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 5℃; Stage #2: propargyl p-toluenesulfonate In tetrahydrofuran at 0 - 25℃; Stage #3: With sodium hydroxide In water for 0.25h;
Stage #1: (R)-1-Aminoindane With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 5℃; Stage #2: propargyl p-toluenesulfonate In tetrahydrofuran at 15 - 20℃;

2,3-dihydro-1H-inden-1-amine (34698-41-4) → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / toluene; water / 4.95 h / 20 - 47 °C / Inert atmosphere; Industry scale 2: isopropyl alcohol; water / 25 °C / Reflux; Inert atmosphere; Industry scale; Resolution of racemate 3: sodium hydroxide / toluene; water / 40 - 47 °C / Industry scale; Inert atmosphere View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 5 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 View Scheme

(1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine L-(+)-tartrate → rasagiline (136236-51-6)

Conditions	Yield
With sodium hydroxide In water; toluene at 40 - 47℃; Industry scale; Inert atmosphere;

inden-1-one (83-33-0) → rasagiline (136236-51-6)

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

N-(2,3-dihydroinden-1-ylidene)prop-2-yn-1-amine (1227784-59-9) → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

N-trifluoroacetyl-(R)-1-aminoindan (155666-94-7) → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: caesium carbonate / acetonitrile; toluene / 30 - 35 °C 2: potassium hydroxide; water / methanol / 0.5 h / 30 - 35 °C View Scheme

(R)-2,3-dihydro-1H-inden-1-amine hydrochloride → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

C14H12F3NO (1378030-60-4) → rasagiline (136236-51-6)

Conditions	Yield
With potassium hydroxide In methanol; water at 30 - 35℃;
With water; potassium hydroxide In methanol at 30 - 35℃; for 0.5h;	14.3 g

N-propargyl-1-aminoindan (1875-50-9) → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.75 h / 25 - 65 °C 2: sodium hydroxide / water / 20 °C View Scheme

indan-1-one oxime (68253-35-0, 100485-57-2, 3349-60-8) → rasagiline (136236-51-6)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 6 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 View Scheme

propargyl bromide (106-96-7) + (R)-2,3-dihydro-1H-inden-1-amine hydrochloride → rasagiline (136236-51-6)

Conditions	Yield
Stage #1: (R)-2,3-dihydro-1H-inden-1-amine hydrochloride With potassium carbonate In acetonitrile at 60 - 62℃; for 1h; Stage #2: propargyl bromide In acetonitrile for 28h; Concentration; Time;	22 g

N-propargyl-1-aminoindan (1875-50-9) → rasagiline (136236-51-6) + N-Propargyl-1(S)-aminoindan

Conditions	Yield
With Chiralcel-OJ-H (4-methylbenzoate cellulose coated on silica) column In ethanol; hexane; diethylamine; isopropyl alcohol at 27℃; Temperature; Solvent; Resolution of racemate;

gluconic acid (526-95-4) + rasagiline (136236-51-6) → R-(+)-N-propargyl-1-aminoindan gluconate (1204184-71-3)

Conditions	Yield
In ethanol; water for 2h; Product distribution / selectivity;	100%
In water; isopropyl alcohol at 40℃; for 1h;

LACTIC ACID (849585-22-4) + rasagiline (136236-51-6) → rasagiline DL-lactate (1260684-39-6)

Conditions	Yield
In acetone for 2h;	100%

propionic acid (802294-64-0) + rasagiline (136236-51-6) → rasagiline propanoate (1260684-10-3)

Conditions	Yield
In di-isopropyl ether for 1.5h;	100%

rasagiline (136236-51-6) + valeric acid (109-52-4) → rasagiline pentanoate (1260684-09-0)

Conditions	Yield
In di-isopropyl ether for 1.5h;	100%

linoleic acid (60-33-3) + rasagiline (136236-51-6) → rasagiline linoleate (1260684-08-9)

Conditions	Yield
In acetone for 2h;	100%

sodium docusate (577-11-7) + rasagiline (136236-51-6) → rasagiline docusate (1260684-42-1)

Conditions	Yield
Stage #1: sodium docusate With hydrogenchloride In dichloromethane; water Stage #2: rasagiline In acetone for 2h; Product distribution / selectivity;	100%

saccharin (81-07-2) + rasagiline (136236-51-6) → rasagiline saccharinate (1260684-40-9)

Conditions	Yield
In acetone	100%
In isopropyl alcohol at 20℃; Cooling with ice;	63%

sodium 4-dodecylbenzenesulfonate (2211-98-5) + rasagiline (136236-51-6) → rasagiline 4-dodecylbenzenesulfonate (1260684-46-5)

Conditions	Yield
With acetic acid In water; acetone for 2h;	100%

benzenesulfonic acid (98-11-3) + rasagiline (136236-51-6) → R-(+)-N-propargyl-1-aminoindan besylate (1201908-33-9)

Conditions	Yield
In toluene at 20℃; Product distribution / selectivity;	99.5%
In ethyl acetate at 10 - 25℃; for 3h; Product distribution / selectivity;

rasagiline (136236-51-6) → [14C]-Rasagiline hydrochloride (136236-50-5)

Conditions	Yield
With hydrogenchloride In tert-butyl methyl ether at 10 - 15℃; for 0.5h; Product distribution / selectivity;	99%
With hydrogenchloride In diethyl ether Product distribution / selectivity; Cooling with ice;
With hydrogenchloride In water; isopropyl alcohol at 40℃; for 2h; Product distribution / selectivity;

hexanoic acid (142-62-1) + rasagiline (136236-51-6) → rasagiline hexanoate (1260684-13-6)

Conditions	Yield
In di-isopropyl ether for 1.5h; Inert atmosphere;	99%

Octanoic acid (124-07-2) + rasagiline (136236-51-6) → rasagiline octanoate (1260684-12-5)

Conditions	Yield
In di-isopropyl ether for 1.5h; Product distribution / selectivity; Inert atmosphere;	99%

hydrogenchloride (7647-01-0) + rasagiline (136236-51-6) → [14C]-Rasagiline hydrochloride (136236-50-5)

Conditions	Yield
In tert-butyl methyl ether at 5 - 10℃; for 0.5h; Solvent; Acidic conditions;	99%

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%

1-decanoic acid (334-48-5) + rasagiline (136236-51-6) → rasagiline decanoate (1260684-11-4)

Conditions	Yield
In di-isopropyl ether for 1.5h; Inert atmosphere;	96%

cis-Octadecenoic acid (112-80-1) + rasagiline (136236-51-6) → rasagiline oleate (1260684-14-7)

Conditions	Yield
In di-isopropyl ether for 1.5h; Product distribution / selectivity; Inert atmosphere;	94%

oxalic acid (144-62-7) + rasagiline (136236-51-6) → (R)-(+)-n-propargyl-1-aminoindane oxalate

Conditions	Yield
In isopropyl alcohol	93.1%

rasagiline (136236-51-6) → (1R)-2,3-dihydro-N-2-propynyl-1H-indane-1-amine hydrobromide (694436-33-4)

Conditions	Yield
With hydrogen bromide In isopropyl alcohol at 5 - 10℃; for 0.5h;	90%
With hydrogen bromide at 25 - 65℃; for 0.5h; Product distribution / selectivity;

hydrogen bromide (10035-10-6, 12258-64-9) + rasagiline (136236-51-6) → (1R)-2,3-dihydro-N-2-propynyl-1H-indane-1-amine hydrobromide (694436-33-4)

Conditions	Yield
In isopropyl alcohol at 5 - 10℃; for 0.5h;	90%

L-Tartaric acid (87-69-4) + rasagiline (136236-51-6) → (1R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine hemihydrate

Conditions	Yield
In isopropyl alcohol at 40℃; for 2.16667h;	88%
In methanol; butanone for 1.16667h; Solvent; Time; Temperature; Reflux;	72%
In isopropyl alcohol at 40℃; for 2h; Product distribution / selectivity;

naphthalene-1,5-disulfonate (81-04-9) + rasagiline (136236-51-6) → di(rasagiline) naphthalene-1,5-disulfonate

Conditions	Yield
In isopropyl alcohol at 20℃; Cooling with ice;	86%

(S)-Mandelic acid (17199-29-0) + rasagiline (136236-51-6) → R-(+)-N-propargyl-1-aminoindane L-(+)-mandelate (1309125-23-2)

Conditions	Yield
In isopropyl alcohol at 20℃; Heating; Cooling with ice;	85%
In n-heptane; isopropyl alcohol
In ethyl acetate; isopropyl alcohol at 20℃; for 24h; Heating;

1-hexadecylcarboxylic acid (57-10-3) + rasagiline (136236-51-6) → (1R)-2,3-dihydro-N-2-propynyl-1H-indane-1-amine palmitate (1260684-23-8)

Conditions	Yield
In isopropyl alcohol at 5 - 10℃; for 0.5h;	85%
In isopropyl alcohol at 5 - 10℃; for 0.5h;	85%

D-Malic acid (636-61-3) + rasagiline (136236-51-6) → rasagiline (D)-malate (1377248-97-9)

Conditions	Yield
In isopropyl alcohol Heating; Cooling with ice;	84%

(1S)-10-camphorsulfonic acid (3144-16-9) + rasagiline (136236-51-6) → rasagiline (1S)-(+)-10-camphorsulfonate (1309125-24-3)

Conditions	Yield
In methanol at 20℃; for 1h;	79%
In n-heptane; isopropyl alcohol

Upstream product

• 496-11-7 INDANE 
• 1175018-73-1 (R)-N-(2-chloroallyl)-2,3-dihydro-1H-inden-1-amine 
• 1224439-21-7 (R)-tert-butyl 2,3-dihydro-1H-inden-1-yl(prop-2-ynyl)carbamate 
• 10277-74-4 (R)-1-Aminoindane 
• 106-96-7 propargyl bromide 
• 26452-98-2 2,3-dihydro-1H-inden-1-yl-acetate 
• 624-65-7 2-propynyl chloride 
• 6351-10-6 1-Indanol 
• 25501-32-0 (S)-indanol 
• 34698-41-4 2,3-dihydro-1H-inden-1-amine 
• 1875-50-9 N-propargyl-1-aminoindan 
• 1227784-59-9 N-(2,3-dihydroinden-1-ylidene)prop-2-yn-1-amine 
• 83-33-0 inden-1-one 
• 16156-58-4 prop-2-yn-1-ol methanesulfonate 

Downstream Products

• 161735-79-1 rasagiline mesylate 
• 1175018-74-2 N-2-propene-1-yl-3-chloro-cis-(R)-aminoindan 
• 1175018-79-7 N-2-propene-1-yl-3-chloro-trans-(R)-aminoindan 
• 1175018-73-1 (R)-N-(2-chloroallyl)-2,3-dihydro-1H-inden-1-amine 
• 124192-86-5 N-Methyl Rasagiline 
• 1313048-99-5 R-(+)-N-propargyl-1-aminoindane salicylate 
• 1309125-23-2 R-(+)-N-propargyl-1-aminoindane L-(+)-mandelate 
• 1309125-28-7 rasagiline D-mandelate 
• 1201908-33-9 R-(+)-N-propargyl-1-aminoindan besylate 
• 694436-34-5 (1R)-2,3-dihydro-N-2-propynyl-1H-inden-1-amine benzoate 
• 164294-86-4 rasagiline tosylate 

Related news

Regular articleEffect of long-term treatment with Rasagiline (cas 136236-51-6) on cognitive deficits and related molecular cascades in aged mice09/07/2019

The present study aimed to investigate the protective effects of prolonged treatment with the selective, irreversible monoamine oxidase-B inhibitor, novel anti-parkinsonian drug, rasagiline (Azilect) in aged animals. Our findings from behavioral experiments demonstrated that long-term treatment ...detailed

Rasagiline (cas 136236-51-6) in Parkinson's Disease09/05/2019

It has long been recognized that monoamine oxidase (MAO) inhibitors have a role in the management of Parkinson's disease (PD). The MAO‐B inhibitor rasagiline has neuroprotective effects in animal models, mediated partly by its antiapoptotic activity. Rasagiline has been shown to be effecti...detailed

Short communicationSimultaneous bioanalysis of Rasagiline (cas 136236-51-6) and its major metabolites in human plasma by LC–MS/MS: Application to a clinical pharmacokinetic study09/04/2019

Rasagiline is a selective, irreversible inhibitor of monoamine oxidase type-B (MAO-B) and has been used both as a monotherapy and in addition to levodopa in the treatment of Parkinson’s disease (PD). Rasagiline is metabolized by the cytochrome P450 (CYP) system, and the following three major me...detailed

Protective effect of Rasagiline (cas 136236-51-6) in aminoglycoside ototoxicity09/03/2019

Sensorineural hearing losses (SNHLs; e.g., ototoxicant- and noise-induced hearing loss or presbycusis) are among the most frequent sensory deficits, but they lack effective drug therapies. The majority of recent therapeutic approaches focused on the trials of antioxidants and reactive oxygen spe...detailed

Chemoenzymatic synthesis of Rasagiline (cas 136236-51-6) mesylate using lipases09/02/2019

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 rac-indanol and an inversion configuration Mitsunobu reaction of the produced (S)-indanol. I...detailed

Data articleSynthesis and characterization of 1-pyrindane derivatives as Rasagiline (cas 136236-51-6) analogues08/30/2019

In this work, the synthesis of several racemic derivatives of 1-pyrindane as rasagiline analogues is described. The 1-pyrindane moiety was functionalised at C-7 position to afford the respective propargyl and isobutyl ethers, propargyl, isopropyl, n-propyl, and cyclopropyl amines and N,N-dimethy...detailed

Rasagiline (cas 136236-51-6) monotherapy in early Parkinson's disease: A phase 3, randomized study in Japan08/29/2019

BackgroundRasagiline is a monoamine oxidase type-B inhibitor in development in Japan for Parkinson's disease (PD). The objective of this Phase 3, randomized, double-blind study was to evaluate the efficacy and safety of rasagiline in Japanese patients with early PD (NCT02337725).detailed

Relevant academic research and scientific papers

A validated normal phase LC method for enantiomeric separation of rasagiline mesylate and its (S)-enantiomer on cellulose derivative-based chiral stationary phase

A simple, sensitive, and robust normal-phase isocratic HPLC-UV method was developed and validated for the enantiomeric separation of rasagiline mesylate and its (S)-enantiomer. The rasagiline and its (S)-enantiomer were resolved on a Chiralcel-OJ-H (4-methylbenzoate cellulose coated on silica) column using a mobile phase consisting of n-hexane:isopropyl alcohol:ethanol:diethyl amine (96:2:2:0.01) at a flow rate of 1.0 ml/min. The column temperature was maintained at 27 °C and elution was monitored at 215 nm. The resolution (Rs) between the enantiomers was found to be more than 2.0. The limit of detection and the limit of quantification of the (S)-enantiomer were found to be 0.35 and 1.05 μg/ml, respectively. The developed method was validated as per ICH guidelines with respect to linearity, limit of detection and quantification, accuracy, precision, and robustness - and satisfactory results were obtained. The sample solution and mobile phase were found to be stable up to 48 h. The method is useful for routine evaluation of the quality of rasagiline mesylate in bulk drug-manufacturing units.

Identification and genotoxicity evaluation of two carbamate impurities in rasagiline

During the synthesis of a second-generation monoamine oxidase-B inhibitor rasagiline, two unknown impurities (impurity A and impurity B) were detected and isolated by preparative liquid chromatography. Based on mass spectroscopy and NMR, these two impurities were characterized as the by-products with a propargyl carbamate structure, whose generation was related to the carbon dioxide in the alkaline reaction solution. Because the carbamate structure has been highlighted as a class of potentially genotoxic impurities (GTIs), the genotoxicity of these two impurities was evaluated by the malformation test and the comet assay using zebrafish embryos. The results showed that the genotoxicity of impurity B was significant higher than that of rasagiline and other impurities. Thus, a HPLC-MS method was developed and validated for the determination of impurity B in rasagiline. The established method showed a good specificity, linearity, precision and accuracy. The detection limit of this method was 2.0?ppm with 0.1 mg ml?1 rasagiline mesylate.

Enantioselective synthesis of 1-aminoindene derivativesviaasymmetric Br?nsted acid catalysis

We describe a catalytic asymmetric iminium ion cyclization reaction of simple 2-alkenylbenzaldimines using a BINOL-derived chiralN-triflyl phosphoramide. The corresponding 1-aminoindenes and tetracyclic 1-aminoindanes are formed in good yields and high enantioselectivities. Further, the chemical utility of the obtained enantiopure 1-aminoindene is demonstrated for the asymmetric synthesis of (S)-rasagiline.

Improved method for preparing rasagiline

The invention provides an improved method for preparing rasagiline, which comprises the following steps: by using a micro-channel reactor, reacting R-(-)-1-aminoindane (structural formula II) servingas a raw material with a propargyl derivative (structural formula III) in the presence of a proper solvent, temperature, alkali and the like to obtain R-(+)-N-propargyl-1-aminoindane (structural formula I), and salifying to obtain rasagiline mesylate. The reaction formula is shown in the specification. According to the method, a dialkyl substitution by-product N,N-dipropargyl-1-aminoindane can bereduced, the rasagiline and the salt thereof can be prepared with a high yield and high purity, the reaction time is shortened, the reaction conditions can resist high temperature and high pressure, the post-treatment is simple, the dialkyl substitution by-product is easy to remove, the unreacted R-(-)-1-aminoindane can be separated and recycled, and the cost is low, and the method is suitable forindustrial production.

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.

CHIRAL CATALYST AND METHOD FOR ASYMMETRIC REDUCTION OF AN IMINE

The present disclosure discusses (i) a compound having a chemical formula according to Formula (I), or its enantiomer; and (ii) a compound that is reactive with a hydride to produce a compound having a chemical formula according to Formula (I), or its enantiomer. Formula (I) is: Formula (I) where R1 and R2 are H, optionally substituted C1-C3 alkyl, or linked together to form an optionally substituted C3 or C4 alkyl group; R3 and R3' are H; R4 and R4' are the same, and are optionally substituted C1-C6 alkyl; and R5 and R5' are the same, and are optionally substituted aryl or heteroaryl. In some examples, R4 and R5 are linked, and R4' and R5' are linked, where both linking groups are the same. The present disclosure also discusses methods of asymmetric reduction of an imine, and methods of forming the catalysts and pre-catalysts.

Kinetic Resolution and Deracemization of Racemic Amines Using a Reductive Aminase

The NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm) was combined with an NADPH oxidase (NOX) to develop a redox system that recycles the co-factor. The AspRedAm-NOX system was applied initially for the kinetic resolution of a variety of racemic secondary and primary amines to yield S-configured amines with enantiomeric excess (ee) values up to 99 %. The addition of ammonia borane to this system enabled the efficient deracemization of racemic amines, including the pharmaceutical drug rasagiline and the natural product salsolidine, with conversions up to >98 % and >99 % ee Furthermore, by using the AspRedAm W210A variant it was possible to generate the opposite R enantiomers with efficiency comparable to, or even better than, the wildtype AspRedAm.

Asymmetric Imine Hydroboration Catalyzed by Chiral Diazaphospholenes

The first use of diazaphospholenes as chiral catalysts has been demonstrated with enantioselective imine hydroboration. A chiral diazaphospholene prepared in a simple three-step synthesis from commercial materials has been shown to achieve the highest enantioselectivity for the hydroboration of alkyl imines with pinacolborane reported to date. Enantiomer ratios of up to 88:12 were obtained with low (2 mol %) catalyst loadings. Twenty examples of asymmetric reduction employing this main-group catalysis protocol, including the synthesis of the pharmaceuticals ent-rasagiline and fendiline, are shown.

PROCESS AND INTERMEDIATES FOR THE RACEMIZATION OF ENANTIOMERICALLY ENRICHED 1-AMINOINDANE

The present invention relates to an improved process for the racemization of (S) -1-aminoindane. (S) -1-aminoindane is formed as a side product in the process of preparation (R) -1-aminoindane by enantiomeric resolution of racemic 1-aminoindane. (R) -aminoindane is a valuable intermediate in the process of preparation of rasagiline.

The impurity of rasagiline mesylate preparation and analysis method

The invention provides a preparation method of an impurity A, an impurity B and an impurity C of rasagiline mesylate and provides a raw medicine for applying a prepared impurity standard product to a rasagiline mesylate product and a quality analysis method of a preparation thereof. Structures of the impurities A, B and C are as shown in the specification.