




































Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 46  

Review Article 

A comprehensive review of disclosures in academic journals regarding the 

synthesis of Rasagiline and its closely related compounds along with major 

biological activity advancements 

Sanjay Sukumar Saralaya 

From, Assistant Professor, Department of Chemistry, Sri Dharmasthala Manjunatheshwara Institute of Technology (SDM IT), 

[Affiliated to Visvesvaraya Technological University (VTU), Belagavi], Ujire, Belthangady Taluk, Dakshina Kannada, Karnataka, 

India. 

ABSTRACT 

This review article was primarily focused to unwind the prior art disclosures about the synthetic strategies adopted for the preparation 

of Rasagiline and its closely related scaffolds. Additionally, some of the major biological activity advancements of Rasagiline and its 

derivatives were also given the priority. It was observed that, propargyl part/ indane part/ or both of Rasagiline was extended through 

numerous synthetic pathways to achieve enhanced biological activity. Additionally, numerous resolution routes were also executed to 

isolate the intended product with high chiral purity. Hence, this review contribution can be a good platform for the worldwide 

researchers to design new routes to synthesize Rasagiline and its structurally close resemblance derivatives.  

Key words: Rasagiline, indane moiety, propargyl moiety, mesylation, resolution, synthesis, isolation.

An overview of the drug information, medical use and (MAO-

B) inhibition. Rasagiline R is a propargylamine based. 

Rasagiline R is a propargylamine based drug prescribed for 

the treatment of idiopathic Parkinson's disease [1, 2]. It has 

been marketed around the globe with the trade names as 

AZIPRON®, AZILECT® tablets, having the active 

pharmaceutical ingredient Rasagiline (as mesylate) along with 

other associated excipients [3]. It is a renowned irreversible 

inhibitor of monoamine oxidase-B (MAO-B) [4-6]. Rasagiline 

mesylate RM  has the IUPAC nomenclature as 1H-inden-1-

amine,2,3-dihydro-N-2-propynyl-(1R)-methanesulfonate with 

an empirical of (C12H13N)CH4SO3 and molecular weight 

(MW: 267.34 g/mol). It is a white to off-white powder, freely 

soluble in water or ethyl alcohol and sparingly soluble in iso-

propyl alcohol [7, 8]. The compound AGN-1135 (N-2-propynyl-

l-indanamine-hydrochloride) was reported to be an irreversible 

MAO-B inhibitor with selectivity in the rat in-vivo [9, 10]. 

Systematic exfoliation of past disclosures 

Numerous synthetic routes were disclosed in various patent 

publications to isolate R and its associated compounds.  

Access this article online 

Received – 29th Mar 2024 

Initial Review – 04th Apr 2024 

Accepted – 07th May 2024 Quick Response Code 

A recent review article was published with details of all 

those patent disclosures towards the synthetic aspects of 

R/RM/RH and its closely related compounds 

(salts/impurities/forms) [11]. This work was selective towards 

the prior art disclosures in academic journals about the 

synthesis and biological activity studies towards R and its 

closely related compounds. Youdim MBH and coworkers had 

disclosed a commercial synthetic route to isolate R and its 

mono-fluorinated derivatives along with an extensive 

biological application studies as Patent applications in United 

States Patent and Trade Mark Office [12, 13]. Lawson WB & 

Rao GJS, had reported the resolution and configurations 

studies of 1-aminoindan or 2,3-dihydro-1H-inden-1-amine 1 

using L-malic acid or 2-hydroxybutanedioic acid 2 in absolute 

ethanol to obtain its optical isomers [14] or the same can be 

achieved by the formation of diastereomeric salts [15].  

NH

CH
H

NH

CH
H

S

O

O OH

CH3

R RM

NH

CH
H

RH

HCl  
Figure 1: Rasagilne R-form and its popular salts. 

__________________________________________________ 

Correspondence to: Sanjay SS, Assistant Professor, 

Department of Chemistry, SDM IT, Opposite to Siddhavana 

Gurukula, Dharmasthala Main Road, Ujire, Belthangady 

Taluk, Dakshina Kannada, Karnataka, India. Email: 

sanjayss@sdmit.in 

mailto:sanjayss@sdmit.in


Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 47  

NH2
1

OH

OO

OH OH

HH

H

2  
Figure 2: Key starting material 1 and the resolving agent 2 

Maruyama W & coworkers had reported the anti-

apoptotic function of R and (1S)-N-(prop-2-yn-1-yl)-2,3-

dihydro-1H-inden-1-amine 3. This initiative had established 

the role of these compounds to suppress the activation of 

caspases and DNA fragmentation [16, 17]. 

NH

CH

3

 
Figure 3: Structure of Rasagiline S-form 

Youdim MBH & coworkers had demonstrated the role of 

R as a selective and potent inhibitor of mitochondrial MAO-B. 

Additionally the work reports the metabolite/s of R 

(metabolite is 1) and N-methyl-N-(1-phenylpropan-2-yl)prop-

2-yn-1-amine; selegiline 4 (metabolites are 1-phenylpropan-2-

amine 5 and N-methyl-1-phenylpropan-2-amine 6 [18].  

N

CH3

CH3

CH
NH2

CH3

4 5
NH

CH3

CH3

6

+
metabolites

R
metabolite

1

Figure 4: Structure of Rasagiline & Selegiline metabolites 

Youdim MBH & coworkers had demonstrated the 

molecular basis of neuroprotective activities of R and three 

other related compounds {((3R)-3-(prop-2-yn-1-ylamino)-2,3-

dihydro-1H-inden-5-yl ethyl (methyl) carbamate 7, (3S)-3-

(prop-2-yn-1-ylamino)-2,3-dihydro-1H-inden-5-yl ethyl 

(methyl) carbamate 8 and 3-[(1R)-1-(dimethylamino) ethyl]-2, 

3-dihydro-1H-inden-5-yl ethyl (methyl) carbamate 9; 

rivastigmine} [19]. Akao Y & coworkers had illustrated the anti-

apoptotic potential of R [20]. 

NH

CH

ON

O

CH3

CH3

7 NH

CH

ON

O

CH3

CH3

8

ON

O

CH3

CH3
CH3

N

CH3

CH3

9

 
Figure 5: Rasagiline related compounds as per [18] 

Maruyama W & coworkers had illustrated the anti-

apoptotic capabilities of four aliphatic compounds like {(2R)-

N-methyl-N-(prop-2-yn-1-yl)heptan-2-amine 10, (2S)-N-

methyl-N-(prop-2-yn-1-yl)heptan-2-amine 11, (2R)-N-(prop-

2-yn-1-yl)heptan-2-amine 12 and 3-[(2R)-heptan-2-

ylamino]propanoic acid 13} [21]. This work was influenced 

by the initiatives from Yu PH & coworkers [22] and Berry 

MD & Boulton AA [23]. 
CH3

N

CH3

CH3

CH

CH3

N

CH3

CH3

CH

CH3

N

H

CH3

CH

CH3

N

H

CH3

O

OH

10 11

12 13

 
Figure 6: Aliphatic amines as per [21] 

Sterling J & coworkers had reported the synthesis, 

characterization and biological activity studies (against 

Alzheimer’s disease) of carbamate derivatives of N-

propargylaminoindans and N-propargylphenethylamines. The 

work had established the fact that, N-methylation of 

propargylamine enhanced the MAO-A & B inhibitory 

activities and decreased the AChE inhibitory activity [24]. 

Maruyama W & coworkers had illustrated the anti-apoptotic 

action determination of R and its derivatives like 7, 8, 9, (3R)-

3-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-inden-5-ol 14 and 

2,3-dihydro-1H-inden-5-yl ethyl(methyl)carbamate 15. The 

experimental outcomes suggested that, anti-apoptotic-

neuroprotective activity was found to reside in the 

propargylamine extension and certainly not in the carbamate 

moiety. In the context, both 7 & 8 were found to be as 

effective as R to protect dopaminergic SH-SY5Y cells against 

apoptosis induced by the peroxynitrite donor. The donated 

compounds used for the experimentation were prepared by 

Teva Pharmaceuticals (Netanya, Israel) [25].  

NH

CH

OH
14

ON

O

CH3

CH3

15

 
Figure 7: Rasagiline related compounds as per [25] 

Yogev-Falach M and coworkers had demonstrated the use 

of 7 & 8 for the treatment of Alzheimer's disease [26]. 

Guillon J & coworkers had demonstrated the multi-step 

synthesis, configurational studies and the preliminary reports 

for MAO-B inhibition by some novel N-propargyl-3-pyrrol-1-

ylindanamine derivatives [27]. Binda C & coworkers had 

reported the complexation, binding mode studies and high-

resolution crystal structure details of four compounds such as 



Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 48  

R, 3, 13 and (1R)-N-methyl-N-(prop-2-yn-1-yl)-2,3-dihydro-

1H-inden-1-amine 16 with MAO-B inhibition studies [28].  

N

CH

CH3

16

 
Figure 8: Rasagiline related compound as per [28]. 

Hubálek F & coworkers had illustrated the spectroscopic 

and the kinetics of inhibitory activity of five compounds such 

as R, 3, 11, 13 & 16. The study outcome suggests that, MAO-

B and MAO-A are more selective towards R than S-enatiomer 

3 by 2500-fold and 17-fold, respectively [29]. Waibel S & 

coworkers had reported the clinical combination of R and 

riluzole to enhance neuroprotective treatment strategies of 

amyotrophic lateral sclerosis (ALS) [30]. Bar-Am O & 

coworkers had illustrated the in-vivo regulation of protein 

kinase-C by R and its derivatives 7 & 8 [31]. Parkinson 

Study Group had established the importance of R based on 

clinical trials to treat Parkinson’s disease [32, 33]. Rascol O 

& coworkers had reported the clinical study details of R in 

comparison with the catecol-O-methytransferase inhibitor, 

entacapone, for the treatment of Parkinson’s disease [34]. 

Youdim MBH & coworkers had compiled a comprehensive 

review article on the pharmacological activity of R and the 

fundamental molecular mechanism behind its neuroprotective 

and neurorescue activities [35].  

O O

N CH3

CH3

N CH3

CH

O O

N CH3

CH3

NH

CH

NH2 NH

CH3

NH CH3

ON

O

CH3

CH3
N

CH3

CH

17 18

1-R isomer

1-S isomer

19

20

21

NH2

NH

CH

OH

22

 
Figure 9: Rasagiline related compounds as per [36]. 

Binda C & coworkers had illustrated the binding of R and its 

related compounds to human MAOs. The work had 

established the crystallographic analysis of complexes and the 

kinetics of inhibition process. The compounds used for the 

studies are R, 1-R isomer, 1-S isomer,  (1R)-1-[methyl(prop-2-

yn-1-yl)amino]-2,3-dihydro-1H-inden-4-yl 

ethyl(methyl)carbamate 17, (1R)-1-(prop-2-yn-1-ylamino)-

2,3-dihydro-1H-inden-4-yl ethyl(methyl)carbamate 18, (1R)-

N-methyl-2,3-dihydro-1H-inden-1-amine 19, (1S)-N-methyl-

2,3-dihydro-1H-inden-1-amine 20, (3R)-3-[methyl(prop-2-yn-

1-yl)amino]-2,3-dihydro-1H-inden-5-yl 

ethyl(methyl)carbamate 21 and (1R)-1-(prop-2-yn-1-ylamino)-

2,3-dihydro-1H-inden-4-ol 22. All the compounds used for the 

tests were received from Teva Pharmaceuticals [36].  

Youdim MBH & coworkers had reported a collective 

review contribution on the therapeutic potential of MAO 

inhibitors, which includes many molecules along with R and 

its related compounds [37]. Oldfield V & coworkers had 

prepared a review article covering all the disclosures of R 

towards its effectiveness to treat Parkinson’s disease [38]. 

Gallagher DA & Schrag A had compiled a review work 

covering the newer pharmacological treatments on the quality 

of patients with Parkinson’s disease. In that coverage, R had 

improved HR-QOL as monotherapy in early Parkinson's 

disease (based on one study). Meanwhile, it was not 

completely in more advanced state of the disease (based on 

one study) [39]. To improve the yield and purity of RM, 

Tatendra RK & coworkers had reported a new process to 

manufacture RM using (1S)-2,3-dihydro-1H-inden-1-ol 23. 

The condensation of 23 with 4-methylbenzenesulfonyl 

chloride 24 was achieved in the presence of 

triethylbenzylammonium chloride (TEBAC), sodium 

hydroxide solution and toluene to isolate (1R)-2,3-dihydro-

1H-inden-1-yl 4-methylbenzenesulfonate 25. It was treated 

with prop-2-yn-1-amine hydrochloride 26 (to be made free 

base by the addition of ammonia solution) under the catalytic 

impact of di-potassium hydrogen phosphate (KH2PO4) and 

TEBAC in toluene to get the residue (crude R). To the residue, 

added isopropyl alcohol and treated with methanesulfonic acid 

(CH3SO3H) to isolate RM. This process was efficient to 

manufacture enatiomerically pure RM in reasonably high 

yield [40].  

OH

+

S OCl

O

CH3

Toluene, H 2O

O S

O

O CH3

CH NH2

.HCl

KH2PO4, TEBAC, Toluene

IPA, CH3SO3H, H2O

NH

CH

.CH3SO3HRM

23

24

25

26

92.0%

79.0%

TEBAC, NaOH

Scheme 1: Route of synthesis to isolate RM from 23 as per 

[40].  

Numerous synthetic routes were reported in prior arts for 

the isolation of R and its salts but the recovery and 



Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 49  

reconversion of unwanted enatiomer 3 was not attempted. In 

this context, Kapubalu SK & coworkers had reported an 

efficient one-pot racemization of 3 with high conversion rate 

and purity. The reported process involves the addition of 

potassium hydroxide and N,N-dimethylsulfoxide (DMSO) to 

the residue comprising the unwanted 3 and heated to 800C. It 

was maintained at the same temperature under agitation for 2 

h and then cooled, quenched to water and extracted with 

dichloromethane (DCM). Upon solvent distillation, light 

brown colored oily mass of R was isolated. This work had 

adopted the process optimization strategy to finalize the above 

mentioned base, solvent and temperature for the efficient 

racemization [41]. This sort of racemization was attempted for 

the first time since the process to isolate the racemic mixture 

of R (free base or as hydrochloride salt) and other related 

compounds were reported by Gittos MW & coworkers [42, 43]. 

NH

CH

3

KOH, DMSO, H 2O, DCM

NH

CH

R

85.0%

Scheme 2: Disclosed resolution pathway of 3 to form R as 

per [41]. 

Alonso N & coworkers had demonstrated the synthesis, 

characterization and the interesting neuroprotective effects of 

some novel carbamate derivatives of R. As per the disclosure, 

(1S,3R)-3-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-inden-1-ol 

27 or (1R,3R)-3-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-

inden-1-ol 32 or (1S,3R)-3-[di(prop-2-yn-1-yl)amino]-2,3-

dihydro-1H-inden-1-ol 35 or (1R,3R)-3-[di(prop-2-yn-1-

yl)amino]-2,3-dihydro-1H-inden-1-ol 38 in acetonitrile was 

treated with dimethylcarbamic chloride 28 or diethylcarbamic 

chloride 29 in the presence of sodium hydride (NaH) to isolate 

eight carbamate derivatives of R. The novel compounds 

isolated are (1R,3S)-3-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-

inden-1-yl dimethylcarbamate 30, (1R,3S)-3-(prop-2-yn-1-

ylamino)-2,3-dihydro-1H-inden-1-yl diethylcarbamate 31, 

(1S,3S)-3-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-inden-1-yl 

dimethylcarbamate 33, (1S,3S)-3-(prop-2-yn-1-ylamino)-2,3-

dihydro-1H-inden-1-yl diethylcarbamate 34, (1S,3R)-3-

[di(prop-2-yn-1-yl)amino]-2,3-dihydro-1H-inden-1-yl 

dimethylcarbamate 36, (1S,3S)-3-(hepta-1,6-diyn-4-yl)-2,3-

dihydro-1H-inden-1-yl diethylcarbamate 37, (1R,3R)-3-

[di(prop-2-yn-1-yl)amino]-2,3-dihydro-1H-inden-1-yl 

dimethylcarbamate 39 and (1R,3R)-3-[di(prop-2-yn-1-

yl)amino]-2,3-dihydro-1H-inden-1-yl diethylcarbamate 40. 

These compounds were tested for the high-throughput 

screening of multitarget drugs in chemical neurosciences. 

Three compounds (34, 36 & 39) had exhibited reasonably 

high neuroprotective effects [44]. This work was inspired 

from González-Díaz H & coworkers, since they disclosed the 

synthesis, characterization and assay of MAO-B inhibitors. 

They synthesized 3-hydroxy, acetate or benzoate derivatives 

mono/di-propargyls starting from benzaldehyde [45]. The 

same team (Luan F & coworkers) had extended their work 

towards the study of 1,3-derivatives of R which are potentially 

useful in neurodegenerative diseases. The derivatives were 

synthesized from benzaldehyde through the multistep 

pathway, they are 27, 32, 35, 38, (1S,3R)-3-[di(prop-2-yn-1-

yl)amino]-2,3-dihydro-1H-inden-1-yl acetate 41, (1R,3R)-3-

[di(prop-2-yn-1-yl)amino]-2,3-dihydro-1H-inden-1-yl acetate 

42, (1S,3R)-3-[di(prop-2-yn-1-yl)amino]-2,3-dihydro-1H-

inden-1-yl benzoate 43 and (1R,3R)-3-[di(prop-2-yn-1-

yl)amino]-2,3-dihydro-1H-inden-1-yl benzoate 44 [46].  

NH

CH

OH

NO

Cl

CH3

CH3

NaH, ACN

NO

Cl

CH3

CH3

NH

CH

O

O

N

CH3

CH3

NH

CH

O

O

N

CH3

CH3

NH

CH

OH

NaH, ACN

NH

CH

O

O

N

CH3

CH3

NH

CH

O

O

N

CH3

CH3

27

28

29

30

31

32

28

29

33

34

Scheme 3a: Synthesis of Rasagilne related compounds as 

per [44-46]. 

Rodríguez-Borges J & coworkers had reported the synthesis 

and characterization of novel propargylated 1-pyrindane 

derivatives. The isolated compounds having close structural 

resemblance to R are 6,7-dihydro-5H-cyclopenta[b]pyridine 1-

oxide 45, 6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate 

46, 6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol 47, 7-(prop-2-

yn-1-yloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine 48, 5,6-

dihydro-7H-cyclopenta[b]pyridin-7-one 49, N-(prop-2-yn-1-

yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine 50 and N,N-

di(prop-2-yn-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-

amine 51 [47]. 



Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 50  

N

CH

OH

CH

NaH, ACN

N

CH

O

O
N CH3

CH3

CH

CH O

O
N

CH3

CH3

CH

N

CH

OH

CH

NaH, ACN

N

CH

O

O
N CH3

CH3

CH

NCH O

O
N

CH3

CH3

CH

35

36

37

38

39

40

28

29

28

29

 
Scheme 3b: Synthesis of Rasagiline related compounds as 

per [44-46]. 

NH
CH

OH

NH
CH

OH

N
CH

OH

CH

N
CH

OH

CH

N
CH

OAc

CH

N
CH

OAc

CH

N
CH

OBz

CH

N
CH

OBz

CH

27 32 35 38

41 42 43 44

 

Figure 10: Rasagiline related compounds as per [44-46]. 

N
+

O
-

N

O

O

CH3

N

OH

N

O

CH

N

O

N

NH

CH

N

N

CH
CH

45 46 47 48 49

50 51

 
Figure 11: Rasagiline related compounds as disclosed by 

[47]. 

Ma G & coworkers had illustrated the novel seven-step 

synthetic route to prepare RM via kinetic resolution (KR) or 

dynamic kinetic resolution (DKR), catalyzed by Candida 

antarctica lipase B (CALB) and palladium-nanocatalyst. 3-

Phenylpropanoic acid 52 was treated with poly phosphoric 

acid (PPA) to isolate 2,3-dihydro-1H-inden-1-one 53. It was 

treated with hydroxylamine hydrochloride (NH2OH. HCl) in 

alkaline medium to get (1E,Z)-N-hydroxy-2,3-dihydro-1H-

inden-1-imine 54. It was reduced under the impact of Pd/C to 

get 1. It was condensed with isopropyl 2-methoxyacetate and 

racemized under special conditions to isolate N-[(1R)-2,3-

dihydro-1H-inden-1-yl]-2-methoxyacetamide 55 and then 1-R 

isomer. It was condensed with propargyl bromide in the 

presence of potassium carbonate (K2CO3) and acetonitrile to 

form R. It was treated with methanesulfonic acid in isopropyl 

alcohol to get RM (overall yield: 25.0%) with an excellent 

enantioselectivity [48]. The reported process was much 

superior to the previous disclosures. The racemization of 1 is 

much superior to the disclosures by Colyer JT & coworkers. 

As per the disclosure, numerous N-tert-butanesulfinyl imines 

were reduced in the presence of sodium borohydride (NaBH4) 

in tetrahydrofuran and water to obtain the corresponding 

secondary sulfinamides in high yield and diastereoselectivity. 

By the use of L-Selectride instead of NaBH4 the 

stereoselectivity was effectively reversed to provide the 

opposite diastereomer product in high yield and selectivity. 

The condensation of 53 with 2-methylpropane-2-sulfinamide 

56 was achieved in the presence of titanium(IV)ethoxide 

{Ti(OEt)4} to isolate N-[(1E,Z)-2,3-dihydro-1H-inden-1-

ylidene]-2-methylpropane-2-sulfinamide 57. It was reduced by 

NaBH4 to isolate N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-

methylpropane-2-sulfinamide 58. The use of L-Selectride for 

the reduction of 57 had resulted in the formation of N-[(1S)-

2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide 

59. Both 58 and 59 distinctly can be brought under the 

influence of hydrochloric acid to isolate respective 1-R isomer 

and 1-S isomer [49]. 

Numerous synthetic pathways were disclosed to prepare 

RM through the formation of 1-R isomer or R. The adopted 

methodologies includes many patents, a few sectorial 

pathways are; the resolution driven chiral acids [41, 50], 

hydrosilylation by the use of chiral rhodium and ruthenium 

catalysts [51-53], asymmetric synthesis using chiral moieties 

[49, 54-57], biocatalyst based deracemization with 

cyclohexylamine oxidase (CHAO) [58], kinetic or dynamic 

kinetic enzymatic resolution [48, 59-62] and configuration 

inversion [40]. To overcome the past chemistry and process 

related issues, Fonseca T de S & coworkers had reported a 

lipase driven chemoenzymatic route to prepare RM. The 

reduction of 53 under the impact of NaBH4 in methanol gave 

(R,S) 2,3-dihydro-1H-inden-1-ol 60. It was acetylated and 

hydrolyzed in the presence of lipase in hexane to obtain 23. 

Further reaction of 23 gave (1R)-1-azido-2,3-dihydro-1H-

indene 62, it was then converted to 1-R isomer. Addition of 



Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 51  

propargyl chloride to 1-R isoler in the presence of K2CO3 and 

acetonitrile gave R. It was treated with methanesulfonic acid 

in isopropyl alcohol resulted in formation of RM. The 

disclosed biocatalytic process was very effective to impart R-

configuration by lipase-mediated kinetic resolution [63]. This 

work was more inspired by the initiatives earlier by 

Fernández R & coworkers [64] and Lin FL & coworkers 

[65]. A review article by Carvalho ACL de M & coworkers 

had covered all the disclosures from 2007-2015 regarding the 

lipase mediated synthesis of drug molecules [66]. 
OHO

PPA

98.2%

O

NH2OH. HCl

NaOH, EtOH, H 2O

89.9%

N

OH

NH2

Pd/C, H2, EtOH

93.5%

CALB, Pd, Toluene

acyl moiety 80.1%

NH
O

O

CH3

NaOH

triethanolamine

76.2%

NH2

propargyl bromide

K2CO3, ACN

59.7%

NH

CH

RM

IPA

methanesulfonic acid

83.1%

52 53 54 1

551-R isomerR

 
Scheme 3a: Disclosed route of synthesis to obtain RM from 

52 as per [48]. 

 

O
53

S

NH2

CH3

CH3

CH3

O

+

56

Ti(OEt) 4

N

SO

CH3

CH3

CH3

NaBH4

NH

SO

CH3

CH3

CH3

HCl
1-R isomer

57 58

84.0%

57
L-Selectride

NH

SO

CH3

CH3

CH3

59

90.0%

HCl
1-S isomer

Scheme 3b: Disclosed route of synthesis to isolate pure 

isomeric forms if 1 as per [49]. 

 

O OH OAc OH

N3NH2

+

RRM

NaBH4

MeOH

86.0%

lipase

hexane

VinOAc

DPPA, DBU

toluene

70.0%

PPh3, KOH

THF, H 2O

70.0%

propargyl chloride

K2CO3, ACN

79.0%

CH3SO3H

IPA

98.0%

53 60 61 23

621-R isomer

Scheme 4: Disclosed route of synthesis to isolate RM from 

53 as per [63]. 

Sousa CAD & coworkers had reported the 

chemical/enzymatic resolution driven synthetic route to 

prepare enantiomerically pure propargyl ethers {(7R)-7-(prop-

2-yn-1-yloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine} 63 and 

{(7S)-7-(prop-2-yn-1-yloxy)-6,7-dihydro-5H-

cyclopenta[b]pyridine} 64. The importance of chiral center in 

R for the biological activity had influenced the isolation of 

these enatiomers in pure form [67]. The same team had earlier 

disclosed the synthesis of racemic mixture of the present 

disclosed compounds [47].  

N

O

CH

N

O

CH

63 64

 
Figure 12: Rasagiline related compounds as per [67]. 

Rizzo-Aguiar F & coworkers had demonstrated the 

synthesis and characterization of some analogues of R. The 

isolated compounds had 1-pyrindane moiety at C-7 position to 

have the respective propargyl 48 and isobutyl 67 ethers, 

propargyl 50, n-propyl 68, isopropyl 69 and cyclopropyl 70 

amines and N,N-dimethyl 65 and diethylcarbamoyl 66 

derivatives [68].  

N

O

N

O

CH3

CH3

N

O

N

O

CH3

CH3

N

O

CH

N

O

CH3

CH3

N

NH

CH

N

NH

CH3

N

NH

CH3

CH3

N

NH

65 66 48 67

50 68 69 70

 
Figure 13: Rasagiline related compounds disclosed as per 

[70]. 

Aguilar N & coworkers had reported the synthesis of the 

R,R-tartrate salt of R using simple, abundant and inexpensive 

chemicals. It was developed with an aim for the practice at 

routine lab sessions (4 h) of undergraduates. The work 

involves the condensation of 1 with propargyl 

benzenesulfonate 71 under alkaline medium in the presence of 

phase transfer catalyst to obtain the racemic oil of drug. The 

crude oily mass was dissolved in methanol/isopropyl alcohol 

and treated with R,R tartaric acid to isolate the solid R-R,R 

tartarate and the other diasteriomer 3-R,R tartarate will be in 

the mother liquor [69]. 

NH2

+

.HCl
S OO

O

CH

NaOH, TBAB, H 2O

NH

CH

tartaric acid

resolution

R-R,R tartarate

+
3-R,R tartarate

avrg yield: 45.0%

Racemic oil1

71

ppt

Scheme 5: Simple route of Rasagiline synthesis from 1 as 

per [69].  



Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 52  

An extended work of the past disclosure [70], Sun Y & 

coworkers had disclosed the identification, characterization 

and synthesis prop-2-yn-1-yl (1R)-2,3-dihydro-1H-inden-1-

ylcarbamate (impurity-A) and prop-2-yn-1-yl (1R)-2,3-

dihydro-1H-inden-1-yl(prop-2-yn-1-yl)carbamate (impurity-

B) of R. It was prepared and isolated by the reaction of 1-R 

isomer with prop-2-yn-1-yl methanesulfonate 71 [71].  

NH2

S

O

O

O

CH3

CH

+
K2CO3

CO2

R +

NH

O

O

CH

+

N

O

O

CH

CH

1-R isomer 71
impurity-A impurity-B

Scheme 6: Disclosed route of synthesis to isolate Rasagiline 

impurities from 1-R isomer as per [71]. 

Brenna D & coworkers had illustrated the flow process to 

isolate 1-R isomer from 53 via imine formation 72R and its 

stereo-selective metal free reduction 73R [72].  

O
53

N

R

HSiCl 3, LB

NH

R

1-R isomer

72R 73R

 

Scheme 7: Preparation of 1-R isomer from 53 as per [72]. 

Matzel P & coworkers had reported the synthesis of R, 3 

and other compounds (selegiline and pramipexole) in a single 

step asymmetric synthesis by reductive amination in the 

presence of imine reductases (IRs). This method is an efficient 

route for the synthesis of pharmaceutically active scaffolds 

comprising chiral secondary and tertiary amines [73]. 

O
53

NH2 CH+
IR-14

58%
R

O
53

NH2 CH+
IR-Sip

81%
3

 

Scheme 8: Synthesis of Rasagiline & its S-isomer from 53 

as per [73]. 

Raju NM & coworkers had reported the synthesis and 

structural elucidation of some major impurities of R. 

Treatment of 53 with ammonium formate (HCO2NH4) and 

reduction from zinc dust gave 1. The addition of 3-

bromoprop-1-ene to 1 in the presence of potassium carbonate 

in acetonitrile had resulted in the formation of N-(prop-2-en-1-

yl)-2,3-dihydro-1H-inden-1-amine 74 (low yield and purity). 

In another example, 53 in chloroform was treated with N-

bromo succinamide in the presence azobisisobutyronitrile to 

get 3-bromo-2,3-dihydro-1H-inden-1-one 75. It was 

condensed with prop-2-yn-1-amine hydrobromide in the 

presence of potassium carbonate in acetonitrile to obtain 3-

(prop-2-yn-1-ylamino)-2,3-dihydro-1H-inden-1-one 76. In 

another demonstration, RS was treated with Lindlar’s catalyst 

in the presence of pyridine to isolate 74 (good yield and 

purity). Similarly, the treatment of RS with D-tartaric acid in 

alcohol medium resulted in the isolation of 3. In line to the 

context, treatment of RS with concentrated hydrochloric acid 

gave two products like N-(2-chloroprop-2-en-1-yl)-2,3-

dihydro-1H-inden-1-amine 77 and N-[(2E,Z)-3-chloroprop-2-

en-1-yl]-2,3-dihydro-1H-inden-1-amine 78 [74].  

O
53

O
53

HCO 2NH4/Zn/CH 3OH

NH2

K2CO3/CH3CN

CH2

Br NH

CH2

NBS/AIBN, CHCl 3

O

Br

K2CO3/CH3CN

CH

NH2

. HBr

NH

CH

O

1 74

75 76

Scheme 9a: Synthesis of Rasagiline related compounds as 

per [74]. 

NH

CH

RS

Lindlar catalyst

Pyridine/CH 3OH
74

D-tartaric acid

IPA/CH3OH
3

Lindlar catalyst

Pyridine/CH 3OH

NH

CH2

Cl

+ NH

Cl

77 78

Scheme 9b: Synthesis of Rasagiline related compounds as 

per [74]. 

Sun H & coworkers had reported a review article about 

the use of various biocatalysts like reductases, oxidases, 

hydrolases, lyases, isomerases and transaminases for the 

preparation of active pharmaceutical ingredients including R 

[75]. This work includes the details furnished in the previous 

disclosure regarding the chemo-enzymatic pathway to 

synthesize R [63]. Albarrán-Velo J & coworkers had 



Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 53  

contributed a review article regarding the use of bio-catalysts 

for the stereo-selective asymmetric synthesis of active 

pharmaceutical ingredients [76]. This work had highlighted 

some of the past initiatives [66, 67, 73] towards the synthesis 

of R via bio-catalysm pathway. Galvão WS & coworkers had 

reported the kinetic resolution of secondary alcohols 

(including 60 to isolate the intermediate for R synthesis) using 

nano-hydrid bio-catalysts [77]. 

OH OH

+

OAc

Fe3O4@APTES-GLU-PF

Vin OAc, hexane

60 23 61

Scheme 10: Resolution pathway to isolate 23 and 61 from 

60 as per [77]. 

Xiao X & coworkers had demonstrated the design, 

synthesis and biological activity estimation of several 

derivatives of R having various linkers like -OCH2-, -SCH2-, -

OCH2CH2-, -OCH2CH2O-, -OCH2CH2CH2O- etc. This work 

had established 79 (D14) as the promising derivative with a 

similar inhibitory activity as R with an improved iso-form 

selectivity [78]. 

NH

O

CH

NH

O

Cl

79

Figure 14: Rasagiline related compound 79 disclosed as 

per [78]. 

Pérez-Venegas M & coworkers had the use of Candida 

antarctica Lipase B (CALB) in the kinetic resolution of 

racemic chiral amines. This work had contributed to an 

efficient and easily scalable process to manufacture R with 

high chiral purity. This disclosure involves the conversion of 1 

to 3 and N-[(1R)-2,3-dihydro-1H-inden-1-yl]acetamide 80 by 

the use of ethyl acetate and prop-2-yn-1-yl methanesulfonate. 

Aqueous HCl treatment to 80 and then the reaction with prop-

2-yn-1-yl methanesulfonate gave R [79].  

Avila-Ortiz CG & coworkers had reported a review 

article regarding the utility of mechanochemistry in enantio-

selective synthesis. This work had emphasized the role of 

enzymes for the resolution of amino acids and amines [80], 

thus covering the past disclosure to prepare R [79]. El-

Shorbagi A-N & coworkers had contributed a comprehensive 

review article on the management of Parkinson’s disease 

(PD), enriched with drug discovery and pharmacological 

approaches of numerous PD specific drugs [81]. Guieu B & 

coworkers had demonstrated the synthesis, characterization 

and biological activity studies of racemic trans-

Propargylamino-Donepezil 81 [82]. 

NH2

Candida antarctica Lipase B (CALB)

AcOEt, Dioxane

CH

O

S
CH3

O

O

NH

CH3

O

+

NH

CH

1 380

aq. HCl, reflux

1-R isomer

R  
Scheme 11: Synthesis of R from 1 as per [79]. 

O
CH3

O

CH3

O

NH

CH

N

81

 
Figure 15: Rasagiline related compound 81 disclosed as 

per [82]. 

Li J & coworkers had illustrated the synthesis of chiral 

helic[1]triptycene[3]arenes and their enantio-selective 

recognition towards chiral aminoindan groups like 1 R-isomer, 

1 S-isomer, R and 3 [83]. Ramachandran PV & coworkers 

had reported the synthesis of racemic R from 53 using the 

specific catalyst system {(CH3O)3B and ammonia-borane} 

[84]. 

O

+

CH

NH2

(CH3O)3B, ammonia-borane

92%
Racemic R

53

Scheme 12: Synthesis of racemic Rasagiline from 53 as per 

[84]. 

Ying P & coworkers had reported a review article 

regarding the pathway of liquid-assisted grinding 

mechanochemistry in the synthesis of active pharmaceutical 

ingredients. This article had covered the preparation of R and 

its S-isomer 3 from 1 [85].  Zhang K & coworkers had 

demonstrated the use of AcRedAm through rational design to 

obtain highly stereo-selective mutants. The best mutant 

formed could synthesize R from 53 in moderate yield with 

high enantiomeric purity [86]. Dugarte-Dugarte AJ & 

coworkers had illustrated the characteristic hydrogen bonding 

patterns and C-H....π interactions in the structure of RM was 



Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 54  

determined using laboratory and synchrotron X-ray powder 

diffraction data aided with DFT calculations [87]. 

Summary 

This review contribution was empowered with twelve reaction 

schemes (Scheme 1 to 12) being furnished for a better 

understanding of the synthetic pathways disclosed by various 

researchers. Similarly, eighty one compounds (Figure 1 to 15) 

were sequentially numbered to provide a systematic flow for 

the disclosed compounds related to R. In most of the 

circumstances, academic journal disclosures are given the 

priority during the literature survey by excluding the contents 

published in patents. Hence, an exclusive patent focused 

contribution was furnished towards the synthesis of R [11]. 

This review article was focused mainly on the academic 

disclosures towards the synthesis of R and its close 

resemblance scaffolds.  

CONCLUSION 

This review article provides a glimpse of disclosed details in 

prior arts towards the synthesis of Rasagiline and some of its 

close resemblance scaffolds. This work had given the 

importance to exfoliate the disclosed information from the 

academic journals and hence patents are intentionally 

excluded.  This work could serve as a vital template for the 

researchers around the globe to design the synthesis of 

scaffolds related to Rasagiline core moiety. In recent times, 

special emphasis was given by the researchers to adopt green 

chemistry pathway for the synthesis of Rasagiline with high 

enantio-selectivity.  

REFERENCES 

1. Sterling J, Veinberg A, Lerner D, et al. (R)(+)-N-Propargyl-1-

aminoindan (rasagiline) and derivatives: highly selective and 

potent inhibitors of monoamine oxidase B. In: MAO-The Mother 

of all Amine Oxidases. Vienna: Springer Vienna; 1998; 301–5.  

2. Chen JJ, Pahwa R. Pharmacologic management of Parkinson 

disease: Choice of initial therapy in early disease. J Pharm Pract. 

2008; 21(4):244–53. 

3. Market Research Intellect. Rasagiline Mesylate API Market size, 

scope and forecast report. Market Research Intellect® | Market 

Analysis and Research Reports. Market Research Intellect. 

Available from: https://www.marketresearchintellect.com/downl 

oad-sample/?rid=935404&utm_source=Pulse&utm_medium=017 

4. Lecht S, Haroutiunian S, Hoffman A, et al. Rasagiline - a novel 

MAO B inhibitor in Parkinson’s disease therapy. Ther Clin Risk 

Manag. 2007; 3(3):467–74.  

5. Chen JJ, Wilkinson JR. The monoamine oxidase type B inhibitor 

rasagiline in the treatment of Parkinson disease: Is tyramine a 

challenge? J Clin Pharmacol. 2012; 52(5):620–8. 

6. Finberg JPM, Rabey JM. Inhibitors of MAO-A and MAO-B in 

psychiatry and neurology. Front Pharmacol. 2016; 7. 

7. PubChem. Rasagiline. Nih.gov. Available from: https 

://pubchem.ncbi.nlm.nih.gov/compound/Rasagiline 

8. Rasagiline. Drugcentral.org. Available from: 

https://drugcentral.org/drugcard/3521 

9. Kalir A, Sabbagh A, Youdim MB. Selective acetylenic “suicide” 

and reversible inhibitors of monoamine oxidase types A and B. 

Br J Pharmacol. 1981; 73(1):55–64. 

10. Finberg JP, Tenne M, Youdim MB. Tyramine antagonistic 

properties of AGN 1135, an irreversible inhibitor of monoamine 

oxidase type B. Br J Pharmacol. 1981; 73(1):65–74. 

11. Saralaya SS. An overview of prior patents for the sequential 

progress in the synthetic approaches of Rasagiline, its salts, 

crystallographic forms and impurities. Indian J Pharm Drug 

Studies. 2023; 2(4):132–47.  

12. Youdim MBH, Finberg JPM, Levy R, et al. R-enantiomers of N-

propargyl-aminoindan compounds, their preparation and 

pharmacyeutical compositions containing them. US Patent.1995; 

5457133. 

13. Sterling J, Levy R, Veinberg A, et al. Monofluorinated 

derivatives of N-propargyl-1-aminoindan and their use as 

inhibitors of monoamine oxidase. US Patent. 1996; 5486541. 

14. Lawson WB, Rao GJS. Specificity in the alkylation of 

methionine at the active site of alpha.-chymotrypsin by aromatic 

.alpha.-bromo amides. Biochemistry. 1980; 19(10):2133–9. 

15. Jacques J, Collet A, Wilen SH. Enantiomers, Racemates and 

Resolutions. Nashville, TN: John Wiley & Sons. 1981. 

16. Maruyama W, Akao Y, Youdim MBH, et al. Neurotoxins induce 

apoptosis in dopamine neurons: protection by N-propargylamine-

1(R)- and (S)-aminoindan, rasagiline and TV1022. In: Advances 

in Research on Neurodegeneration. Vienna: Springer Vienna. 

2000; 171–86. 

17. Maruyama W, Youdim MBH, Naoi M. Antiapoptotic properties 

of rasagiline, N‐propargylamine‐1 (R)‐ aminoindan, and its 

optical (S)‐isomer, TV1022. Ann N Y Acad Sci. 2001; 

939(1):320–9. 

18. Youdim MBH, Gross A, Finberg JP. Rasagiline [N-propargyl-

1R(+)-aminoindan], a selective and potent inhibitor of 

mitochondrial monoamine oxidase B: Rasagiline, a selective 

inhibitor of MAO-B. Br J Pharmacol. 2001; 132(2):500–6. 

19. Youdim MBH, Weinstock M. Molecular basis of neuroprotective 

activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-

propargyl-(3R) aminoindan-5-YL)-ethyl methyl carbamate]. Cell 

Mol Neurobiol. 2001; 21(6):555–73. 

20. Akao Y, Maruyama W, Shimizu S, et al. Mitochondrial 

permeability transition mediates apoptosis induced by N‐methyl 

(R) salsolinol, an endogenous neurotoxin, and is inhibited by 

Bcl‐2 and rasagiline, N‐propargyl‐1 (R)‐aminoindan. J 

Neurochem. 2002; 82(4):913–23. 

21. Maruyama W, Boulton AA, Davis BA, et al. Enantio-specific 

induction of apoptosis by an endogenous neurotoxin, N -

methyl(R) salsolinol, in dopaminergic SH-SY5Y cells: 

suppression of apoptosis by N-(2-heptyl)-N-methylpro-

pargylamine. J Neural Transm (Vienna). 2001; 108(1):11–24. 

22. Yu PH, Davis BA, Boulton AA. Aliphatic propargylamines, a 

new series of potent selective, irreversible non-amphetamine-like 

MAO-B inhibitors. In: Neurochemistry in Clinical Application. 

Boston, MA: Springer US. 1995; 17–23. 

23. Berry MD, Boulton AA. Aliphatic propargylamines as 

symptomatic and neuroprotective treatments for neurodege-

nerative diseases. Neurotoxicol Teratol. 2002; 24(5):667–73. 

24. Sterling J, Herzig Y, Goren T, et al. Novel dual inhibitors of 

AChE and MAO derived from hydroxy aminoindan and 

https://www.marketresearchintellect.com/download-sample/?rid=935404&utm_source=Pulse&utm_medium=017
https://www.marketresearchintellect.com/download-sample/?rid=935404&utm_source=Pulse&utm_medium=017
https://pubchem.ncbi.nlm.nih.gov/compound/Rasagiline
https://pubchem.ncbi.nlm.nih.gov/compound/Rasagiline
https://drugcentral.org/drugcard/3521


Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 55  

phenethylamine as potential treatment for Alzheimer’s disease. J 

Med Chem. 2002; 45(24):5260–79. 

25. Maruyama W, Weinstock M, Youdim MBH, et al. Anti-apoptotic 

action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-

aminoindan-5-yl]-ethyl methyl carbamate, a novel 

cholinesterase-monoamine oxidase inhibitor. Neurosci Lett. 

2003; 341(3):233–6. 

26. Yogev-Falach M, Amit T, Bar-Am O, et al. The involvement of 

mitogen‐activated protein (MAP) kinase in the regulation of 

amyloid precursor protein processing by novel cholinesterase 

inhibitors derived from rasagiline. FASEB J. 2002; 16(12):1674–6. 

27. Guillon J, Hébert G, Dallemagne P, et al. Synthesis and initial 

results for MAO-B inhibition by new N-propargyl-3-pyrrol-1-

ylindanamine derivatives, analogues of rasagiline. J Enzyme 

Inhib Med Chem. 2003; 18(2):147–53. 

28. Binda C, Hubálek F, Li M, et al. Crystal structures of monoamine 

oxidase B in complex with four inhibitors of the N-

propargylaminoindan class. J Med Chem. 2004; 47(7):1767–74. 

29. Hubálek F, Binda C, Li M, et al. Inactivation of purified human 

recombinant monoamine oxidases A and B by rasagiline and its 

analogues. J Med Chem. 2004; 47(7):1760–6. 

30. Waibel S, Reuter A, Malessa S, et al. Rasagiline alone and in 

combination with riluzole prolongs survival in an ALS mouse 

model. J Neurol. 2004; 251(9). 

31. Bar-Am O, Yogev-Falach M, Amit T, et al. Regulation of protein 

kinase C by the anti‐Parkinson drug, MAO‐B inhibitor, rasagiline 

and its derivatives: In vivo. J Neurochem. 2004; 89(5):1119–25. 

32. Parkinson Study Group. A controlled, randomized, delayed-start 

study of rasagiline in early Parkinson disease. Arch Neurol. 2004; 

61(4):561. 

33. Parkinson Study Group. A randomized placebo-controlled trial of 

rasagiline in levodopa-treated patients with Parkinson disease and 

motor fluctuations: The PRESTO study. Arch Neurol. 2005; 

62(2):241. 

34. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct 

to levodopa in patients with Parkinson’s disease and motor 

fluctuations (LARGO, Lasting effect in Adjunct therapy with 

Rasagiline Given Once daily, study): A randomised, double-

blind, parallel-group trial. Lancet. 2005; 365(9463):947–54. 

35. Youdim MBH, Maruyama W, Naoi M. Neuropharmacological, 

neuroprotective and amyloid precursor processing properties of 

selective MAO-B inhibitor antiparkinsonian drug, rasagiline. 

Drugs Today (Barc). 2005; 41(6):369. 

36. Binda C, Hubálek F, Li M, et al. Binding of rasagiline-related 

inhibitors to human monoamine oxidases: A kinetic and 

crystallographic analysis. J Med Chem. 2005; 48(26):8148–54. 

37. Youdim MBH, Edmondson D, Tipton KF. The therapeutic 

potential of monoamine oxidase inhibitors. Nat Rev Neurosci. 

2006; 7(4):295–309. 

38. Oldfield V, Keating GM, Perry CM. Rasagiline: A Review of its 

Use in the Management of Parkinson’s Disease. Drugs. 2007; 

67(11):1657–79. 

39. Gallagher DA, Schrag A. Impact of newer pharmacological 

treatments on quality of life in patients with Parkinson???S 

disease. CNS Drugs. 2008; 22(7):563–86. 

40. Tatendra RK, Suneel KK, Omprakash G, et al. A new process for 

the synthesis of enantiomerically pure R-(+)-N- propargyl-1-

aminoindan mesylate(Rasagiline mesylate). Derpharmachemica. 

2011. Available from: https://www.derpharmachemica.com/ 

pharma-chemica/a-new-process-for-the-synthesis-of-enantiome 

rically-pure-rnpropargyl1aminoindan-mesylaterasagiline-

mesylate.pdf 

41. Kapubalu SK, Kovvuri TR, Gunnam JMR, et al. An efficient 

single-pot racemization of s (-) rasagiline: A byproduct of anti-

Parkinson’s drug. Globalresearchonline.net. Available from: 

https://www.globalresearchonline.net/journalcontents/v12-

1/029.pdf 

42. Gittos MW, James JW, Wiggins LF. Derivatives of 1-

aminoindane. GB Patent. 1966; 1037014A. 

43. Gittos MW, James JW, Wiggins LF. Methods of lowering blood 

pressure in animals by administering secondary and tertiary 

amines. US Patent. 1970; 3513244. 

44. Alonso N, Caamaño O, Romero-Duran FJ, et al. Model for high-

throughput screening of multitarget drugs in chemical 

neurosciences: Synthesis, assay, and theoretic study of rasagiline 

carbamates. ACS Chem Neurosci. 2013; 4(10):1393-403. 

45. González-Díaz H, Prado-Prado F, García-Mera X, et al. MIND-

BEST: Web server for drugs and target discovery; Design, 

synthesis, and assay of MAO-B inhibitors and 

Theoretical−Experimental study of G3PDH protein from 

Trichomonas gallinae. J Proteome Res. 2011; 10(4):1698–718. 

46. Luan F, Cordeiro MNDS, Alonso N, et al. TOPS-MODE model 

of multiplexing neuroprotective effects of drugs and 

experimental-theoretic study of new 1,3-rasagiline derivatives 

potentially useful in neurodegenerative diseases. Bioorg Med 

Chem. 2013; 21(7):1870–9. 

47. Rodríguez-Borges J, Pereira C, Salgado S, et al. Synthesis of new 

propargylated 1-pyrindane derivatives as rasagiline analogues. 

Synlett. 2013; 24(07):837–8. 

48. Ma G, Xu Z, Zhang P, et al. A novel synthesis of rasagiline via a 

chemoenzymatic dynamic kinetic resolution. Org Process Res 

Dev. 2014; 18(10):1169-74. 

49. Colyer JT, Andersen NG, Tedrow JS, et al. Reversal of 

diastereofacial selectivity in hydride reductions of N-tert-

butanesulfinyl imines. J Org Chem. 2006; 71(18):6859–62. 

50. Lidor R, Bahar E, Zairi O, et al. A facile synthesis for racemic 

and optically active 1-aminoindans. Org Prep Proced Int. 1997; 

29(6):701–6. 

51. Brunner H, Becker R, Gauder S. Asymmetric catalysis. 29. 

Optically active primary amines by enantioselective catalytic 

hydrosilylation of ketoximes. Organometallics. 1986; 5(4):739–

46. 

52. Takei I, Nishibayashi Y, Ishii Y, et al. Ruthenium-catalysed 

asymmetric hydrosilylation of ketoximes using chiral 

oxazolinylferrocenylphosphines. Chem Commun (Camb). 2001; 

(22):2360–1. 

53. Reddy RP, Davies HML. Dirhodium tetracarboxylates derived 

from adamantylglycine as chiral catalysts for enantioselective 

C−H aminations. Org Lett. 2006; 8(22):5013–6. 

54. Gutman AL, Etinger M, Nisnevich G, et al. Stereo- and 

regioselectivity in asymmetric synthesis of α-amino substituted 

benzocyclic compounds. Tetrahedron Asymmetry. 1998; 

9(24):4369–79. 

55. Juaristi E, León-Romo JL, Reyes A, et al. Recent applications of 

α-phenylethylamine (α-PEA) in the preparation of enantiopure 

compounds. Part 3: α-PEA as chiral auxiliary. Part 4: α-PEA as 

chiral reagent in the stereodifferentiation of prochiral substrates. 

Tetrahedron Asymmetry. 1999; 10(13):2441–95. 

56. Uiterweerd PGH, van der Sluis M, Kaptein B, et al. (S)-1-

Aminoindane: synthesis by chirality transfer using (R)-

phenylglycine amide as chiral auxiliary. Tetrahedron 

Asymmetry. 2003; 14(22):3479–85. 

https://www.derpharmachemica.com/%20pharma-chemica/a-new-process-for-the-synthesis-of-enantiome%20rically-pure-rnpropargyl1aminoindan-mesylaterasagiline-mesylate.pdf
https://www.derpharmachemica.com/%20pharma-chemica/a-new-process-for-the-synthesis-of-enantiome%20rically-pure-rnpropargyl1aminoindan-mesylaterasagiline-mesylate.pdf
https://www.derpharmachemica.com/%20pharma-chemica/a-new-process-for-the-synthesis-of-enantiome%20rically-pure-rnpropargyl1aminoindan-mesylaterasagiline-mesylate.pdf
https://www.derpharmachemica.com/%20pharma-chemica/a-new-process-for-the-synthesis-of-enantiome%20rically-pure-rnpropargyl1aminoindan-mesylaterasagiline-mesylate.pdf
https://www.globalresearchonline.net/journalcontents/v12-1/029.pdf
https://www.globalresearchonline.net/journalcontents/v12-1/029.pdf


Saralaya                                                                  An overview on the synthesis of Rasagiline and its related scaffolds                

Vol 3 | Issue 2 | Apr – Jun 2024                                                                                     Indian J Pharm Drug Studies | 56  

57. Pakulski MM, Mahato SK, Bosiak MJ, et al. Enantioselective 

reduction of ketoxime ethers with borane–oxazaborolidines and 

synthesis of the key intermediate leading to (S)-rivastigmine. 

Tetrahedron Asymmetry. 2012; 23(9):716–21. 

58. Leisch H, Grosse S, Iwaki H, et al. Cyclohexylamine oxidase as a 

useful biocatalyst for the kinetic resolution and dereacemization 

of amines. Can J Chem. 2012; 90(1):39–45. 

59. Gutman AL, Meyer E, Kalerin E, et al. Enzymatic resolution of 

racemic amines in a continuous reactor in organic solvents. 

Biotechnol Bioeng. 1992; 40(7):760–7. 

60. Gutman AL, Shkolnik E, Meyer E, et al. Practical enzymatic 

resolution of racemic alcohols and amines in organic solventsa. 

Ann N Y Acad Sci. 1996; 799(1):620–32. 

61. Malik MS, Park E-S, Shin J-S. ω-Transaminase-catalyzed kinetic 

resolution of chiral amines using l-threonine as an amino 

acceptor precursor. Green Chem. 2012; 14(8):2137. 

62. Päiviö M, Perkiö P, Kanerva LT. Solvent-free kinetic resolution 

of primary amines catalyzed by Candida antarctica lipase B: 

Effect of immobilization and recycling stability. Tetrahedron 

Asymmetry. 2012; 23(3-4):230–6. 

63. Fonseca T de S, Silva MR da, de Oliveira M da CF, et al. 

Chemoenzymatic synthesis of rasagiline mesylate using lipases. 

Appl Catal A Gen. 2015; 492:76–82. 

64. Fernández R, Ros A, Magriz A, et al. Enantioselective synthesis 

of cis-α-substituted cycloalkanols and trans-cycloalkyl amines 

thereof. Tetrahedron. 2007; 63(29):6755–63. 

65. Lin FL, Hoyt HM, van Halbeek H, et al. Mechanistic 

investigation of the Staudinger ligation. J Am Chem Soc. 2005; 

127(8):2686–95. 

66. Carvalho ACL de M, Fonseca T de S, de Mattos MC, et al. 

Recent advances in lipase-mediated preparation of 

pharmaceuticals and their intermediates. Int J Mol Sci. 2015; 

16(12):29682–716. 

67. Sousa CAD, Sampaio-Dias IE, Rizzo-Aguiar F, et al. 

Enantiopure synthesis of 7-(1-pyrindanyl)propargyl ethers as 

rasagiline analogues via chemical or enzymatic resolution of 1-

pyrindan-7-ol. RSC Adv. 2015; 5(126):104509–15. 

68. Rizzo-Aguiar F, Sousa CAD, Garcia-Mera X, et al. Synthesis and 

characterization of 1-pyrindane derivatives as rasagiline 

analogues. Chem Data Coll. 2016; 5(6):21–7. 

69. Aguilar N, Garcia B, Cunningham M, et al. Synthesis of a 

Parkinson’s disease treatment drug, the R,R-tartrate salt of R-

rasagiline: A three week introductory organic chemistry lab 

sequence. J Chem Educ. 2016; 93(5):937–40. 

70. Sun Y, Yan Y, Feng X, et al. Preparation method of rasagiline 

and analogue thereof. Patent. 2014; Available from: 

https://patents.google.com/patent/ 

CN103804200A/en?oq=+CN103804200A 

71. Sun Y, Zhang X, Yan Y, et al. Identification and genotoxicity 

evaluation of two carbamate impurities in rasagiline. RSC Adv. 

2016; 6(108):106268–74. 

72. Brenna D, Pirola M, Raimondi L, et al. A stereoselective, 

catalytic strategy for the in-flow synthesis of advanced precursors 

of rasagiline and tamsulosin. Bioorg Med Chem. 2017; 

25(23):6242–7. 

73. Matzel P, Gand M, Höhne M. One-step asymmetric synthesis of 

(R)- and (S)-rasagiline by reductive amination applying imine 

reductases. Green Chem. 2017; 19(2):385–9. 

74. Raju NM, Babu JM, Rao BV. Synthesis and characterization of 

impurities in rasagiline: A novel MAO-B inhibitor in Parkinson’s 

disease therapy. Asian J Chem. 2017; 29(6):1357–9. 

75. Sun H, Zhang H, Ang EL, et al. Biocatalysis for the synthesis of 

pharmaceuticals and pharmaceutical intermediates. Bioorg Med 

Chem. 2018; 26(7):1275-84. 

76. Albarrán-Velo J, González-Martínez D, Gotor-Fernández V. 

Stereoselective biocatalysis: A mature technology for the 

asymmetric synthesis of pharmaceutical building blocks. Biocatal 

Biotransformation. 2018; 36(2):102–30. 

77. Galvão WS, Pinheiro BB, Golçalves LRB, et al. Novel 

nanohybrid biocatalyst: application in the kinetic resolution of 

secondary alcohols. J Mater Sci. 2018; 53(20):14121–37. 

78. Xiao X, Zhang X-X, Zhan M-M, et al. Design, synthesis and 

bioevalucation of novel 2,3-dihydro-1H-inden-1-amine 

derivatives as potent and selective human monoamine oxidase B 

inhibitors based on rasagiline. Eur J Med Chem. 2018; 145:588–

93. 

79. Pérez-Venegas M, Juaristi E. Mechanoenzymatic resolution of 

racemic chiral amines, a green technique for the synthesis of 

pharmaceutical building blocks. Tetrahedron. 2018; 

74(44):6453–8. 

80. Avila-Ortiz CG, Pérez-Venegas M, Vargas-Caporali J, et al. 

Recent applications of mechanochemistry in enantioselective 

synthesis. Tetrahedron Lett. 2019; 60(27):1749–57. 

81. El-Shorbagi A-N, Chaudhary S, Alshemali KA, et al. A 

comprehensive review on management of Parkinson’s disease, 

inclusive of drug discovery and pharmacological approaches. J 

Appl Pharm Sci. 2020. Available from: http://dx.doi.org/10.7324/ 

japs.2020.1010015 

82. Guieu B, Lecoutey C, Legay R, et al. First synthesis of racemic 

Tran’s propargylamino-donepezil, a pleiotrope agent able to both 

inhibit AChE and MAO-B, with potential interest against 

Alzheimer’s disease. Molecules. 2020; 26(1):80. 

83. Li J, Han Y, Chen C-F. Synthesis of chiral helic [1] triptycene [3] 

arenes and their enantioselective recognition towards chiral 

guests containing aminoindan groups. Molecules. 2021; 

26(3):536. 

84. Ramachandran PV, Choudhary S, Singh A. Trimethyl borate-

catalyzed, solvent-free reductive amination. J Org Chem. 2021; 

86(5):4274–80. 

85. Ying P, Yu J, Su W. Liquid‐assisted grinding mechanochemistry 

in the synthesis of pharmaceuticals. Adv Synth Catal. 2021. 

Available from: http://dx.doi.org/10.1002/adsc.202001245 

86. Zhang K, He Y, Zhu J, et al. Engineering of reductive aminases 

for asymmetric synthesis of enantiopure rasagiline. Front Bioeng 

Biotechnol. 2021; 9. Available from: 

http://dx.doi.org/10.3389/fbioe.2021. 798147 

87. Dugarte-Dugarte AJ, Toro RA, van de Streek J, et al. Hydrogen 

bonding patterns and C-H...π interactions in the structure of the 

antiparkinsonian drug (R)-rasagiline mesylate determined using 

laboratory and synchrotron X-ray powder diffraction data. Acta 

Crystallogr B Struct Sci Cryst Eng Mater. 2023; 79(6):462–72. 
 

How to cite this article: Saralaya SS, A comprehensive 

review of disclosures in academic journals regarding the 

synthesis of Rasagiline and its closely related compounds 

along with major biological activity advancements. 

Indian J Pharm Drug Studies. 2024; 3(2):46-56. 

Funding: None;              Conflicts ofInterest: None Stated 

 

https://patents.google.com/patent/%20CN103804200A/en?oq=+CN103804200A
https://patents.google.com/patent/%20CN103804200A/en?oq=+CN103804200A
http://dx.doi.org/10.7324/%20japs.2020.1010015
http://dx.doi.org/10.7324/%20japs.2020.1010015
http://dx.doi.org/10.1002/adsc.202001245
http://dx.doi.org/10.3389/fbioe.2021.%20798147

