




































Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 132  

Review Article 

An overview of prior patents for the sequential progress in the synthetic 

approaches of Rasagiline, its salts, crystallographic forms and impurities 

Sanjay Sukumar Saralaya 

From, Assistant Professor, Department of Chemistry, Sri Dharmasthala Manjunatheshwara, Institute of Technology, 

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

India. Pin code - 574 240. 

ABSTRACT 

This review work was intended to provide the essential details disclosed in prior patents on the synthesis of Rasagiline, its salts 

(as crystalline or amorphous forms) and a few impurities. Quite a high number of patents were published in various patent 

trademark offices around the world regarding the synthesis of Rasagiline. Among them, the patents which fall under the similar 

family are excluded to prevent the possible duplication of the information. The remaining distinct patents were carefully 

reviewed and the particulars are grouped in chronological order. Moreover, this initiative can provide an essential backyard for 

the global researchers and the organizations to get the details on the methodological flourish of Rasagiline. More importantly, 

the work forms a firm basis for to invent/innovate a few more new strategies to commercialize Rasagiline in its 

pharmaceutically suitable and stable forms. Additionally, researchers can avail the information about the organizations which 

are behind the continuous process improvement on various aspects of Rasagiline.  

Key words: Rasagiline base, Rasagiline mesylate, Propargylation, N-alkylation, Racemization. 

he popular drug, Rasagiline is an irreversible 

inhibitor of monoamine oxidase. It is used widely 

as a monotherapy during the initial stages of 

Parkinson's disease or as an adjunct therapy in more 

advanced scenarios [1, 2]. 

NH
H

S

O

O OH1

 
Rasagiline mesylate (C13H17NO3S) 1 has the IUPAC name: 

[(1R)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine 

methanesulfonate] with a CAS registry number: 161735-

79-1 and a molecular weight: 267.34 g/mol. It is 

commercially marketed under the brand/trade name 

Azilect®. Rasagiline is a renowned propargylamine 

Access this article online 
 

Received – 24th August 2023 

Initial Review – 09th September 2023 

Accepted – 10th October 2023 
 

Quick Response Code 

derivative with a good clinical efficacy. Interestingly, R-

(+)-enantiomer is therapeutically active and hence gained a 

wide clinical importance to treat Parkinson's disease, 

memory disorders and dementia of the Alzheimer type 

(DAT), depression, and hyperactive syndrome in children 

[3]. The S-(-)-enantiomer of Rasagiline has a bit of 

neuroprotective properties but the potency of R-(+)-

enantiomer over the monoamineoxidase enzyme (MAO-B) 

is around 1000-fold higher. However, the racemic 

Rasagiline hydrochloride was discovered in 1970s and was 

effectively used to treat hypertension [4]. After achieving 

the resolution of enantiomers, it was found that R-(+)-

enantiomer was an active MAO-B inhibitor with a 

reasonably high degree of selectivity. Meanwhile, S-(-)-

enantiomer had showed relatively very low MAO-B 

inhibitory activity [5].  

_______________________________________________ 

Correspondence to: Sanjay Sukumar Saralaya, Assistant 

Professor, Department of Chemistry, Sri Dharmasthala 

Manjunatheshwara, Institute of Technology, [Affiliated to 

Visvesvaraya Technological University, Belagavi], Ujire, 

Belthangady Taluk, Dakshina Kannada, Karnataka, India. 

Pincode - 574 240. Email: sanjay.saralaya@gmail.com. 

 

T 

mailto:sanjay.saralaya@gmail.com


Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 133  

Literature review 

A chronological flow was maintained in this review 

initiative to tabulate all the essential process centric details 

disclosed in the prior patents regarding the synthesis, 

racemization, purification, impurity profiling, various 

stable salts of Rasagiline and its crystallograhic forms. 

NH2

2

Br
3 N4

Cl
5

NH2

6

Cl
7

OH13

S

O

O

S

O

O
O

14

S
O

OO

8

O NH9 11 Cl12
NH2

10

Huebner CF., in 1966, had reported the condensation of 1-

amino-indane 2 with propargyl bromide 3 in the presence 

of sodium carbonate and acetone to isolate 1-(N,N-

dipropargyl-amino)-indane hydrochloride 4 with a melting 

point of 160-163oC (yield: 11.82%, recrystallized from 

ethyl alcohol). Furthermore, the condensation of 1-chloro-

indane 5 with propargylamine 6 was achieved in isopropyl 

alcohol to isolate the racemic Rasagiline hydrochloride 

with a melting point of 178-179oC (yield: 22.27%, 

recrystallized from ethyl alcohol) [6].  

Maurice WG, et al., in 1968 & 1970, had demonstrated 

synthesis and applications of N-substituted 1-

aminoindanes. The condensation of 5 with 6 was executed 

in the presence of sodium iodide in ethyl alcohol to isolate 

the racemic Rasagiline hydrochloride with a melting point 

of 185-187oC (recrystallized from isopropyl alcohol). It 

was believed that, N,N-di(1-indanyl)-propargyl amine 

hydrochloride (dimer) had formed as an intermediate [4,7]. 

Youdim MBH, et al., in 1991, 1995 & 1996, had 

illustrated the synthesis and effective resolution of the 

racemic Rasagiline base. Rasagiline base was prepared by 

treating 2 with propargyl chloride 7 in the presence of 

potassium carbonate and acetonitrile. The isolated 

Rasagiline base was treated with ethereal hydrochloride 

(HCl gas purged to diethyl ether) to isolate the Rasagiline 

hydrochloride with a melting point of 182-184oC (yield: 

46.82%, recrystallized from isopropyl alcohol).The 

racemic mixture of Rasagiline base was resolved in a 

preparative HPLC (high performance liquid 

chromatography) column and converted to S-(-)-

enantiomer hydrochloride with a melting point of 182-

184oC (isolated from diethyl ether). Similarly, R-(+)-

enantiomer hydrochloride was isolated with a melting 

point of 179-181oC (isolated from diethyl ether). 

Moreover, the work extends to report the reaction of R-(-)-

enantiomer of 2 with 7 in the presence of potassium 

carbonate and acetonitrile to isolate R-(+)-enantiomer of 

Rasagiline hydrochloride with a melting point of 183-

185oC (yield: 35.18%, recrystallized from isopropyl 

alcohol). Under the similar context, S-(+)-enantiomer of 2 

was reacted with 7 to get S-(-)-enantiomer of Rasagiline 

hydrochloride with a melting point of 183-185oC 

(recrystallized from isopropyl alcohol). Furthermore, R-

(+)-Rasagiline base was treated with L-tartaric acid to 

isolate R-(+)-di-Rasagiline tartarate with a melting point of 

175-177oC (yield: 46.59%, isolated from methyl alcohol). 

In an illustration, propargyl benzenesulfonate 8 was 

reacted with racemic 2 in the presence of aqueous sodium 

hydroxide in toluene to isolate R-(+)-di-Rasagiline 

tartarate. It was treated with methanesulfonic acid in 

isopropyl alcohol to isolate 1 with a melting point of 

157oC. [5,8-11].  

Gutman AL, et al., in 2002, had reported the condensation 

of 2,3-dihydro-1H-1-indanone 9 with benzylamine 10 in 

the presence of acetic acid and benzene to form the 

important imine intermediate. It was reduced using sodium 

borohydride in ethyl alcohol and treated with sodium 

hydroxide solution to isolate the racemic N-benzyl-2,3-

dihydro-1H-inden-1-amine 11 with a boiling point of 125-

135oC (yield: 82%, purity: 95.9% by gas chromatography-

https://patents.google.com/?inventor=Huebner+Charles+Ferdinand


Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 134  

GC). In an alternate pathway, that involved the 

condensation of 1-chloro-2,3-dihydro-1H-indene 12 with 

10 in acetonitrile to isolate racemic 11 with a boiling point 

of 125-135oC (yield: 64%) [12]. It was resolved under the 

influence of R,R-tartaric acid in water to isolate the crude 

salt. It was recrystallized from water to isolate the R,R-

tartarate salt of 11 with a melting point of 135-144oC 

(yield: 32%). S-isomer of 11 was recovered and resolved 

using potassium-t-butoxide in dimethylsulfoxide to isolate 

11 (yield: 80%). R,R-tartarate salt of 11 was reduced using 

palladium-carbon in water to isolate R-isomer of 2 with a 

boiling point of 130-140oC (yield: 72%). This can also be 

treated with 3 or 7 to isolate Rasagiline base as per the past 

disclosures [12].  

Lee TB, et al., in 2006, had demonstrated the condensation 

of S-1-indanol 13 with 6 in the presence of 

methanesulfonyl anhydride 14 and triethylamine in 

dichloromethane to isolate the R-Rasagiline base (yield: 

68%, as brown liquid) [13]. 

Anton F, et al., in 2007 & 2009, had illustrated the 

reaction of 2 with 8 in the presence of aqueous sodium 

hydroxide in toluene to isolate Rasagiline base through the 

extraction method (yield: 66.71%, as brown oil). It was 

treated with L-tartaric acid in isopropyl alcohol to isolate 

R-Rasagiline tartarate with a melting point of 176.3-

176.8oC (yield: 28.8%, S-isomer: approx. 4%). With the 

use of similar key reagents, an additional two illustrations 

were reported. They are, direct and prolonged precipitation 

methods to isolate Rasagiline tartarate with the melting 

points in the range of 160.8-163.2oC having the S-isomer 

content to about 4-16%. The work had even disclosed a 

few other precipitation methods such as, Rasagiline sulfate 

isolation, recrystallization of Rasagiline salts from 

solvents/water and salt inter-conversions etc [14, 15]. 

N OH
15 N16 NH NH17 18 NH

O

19

Luo JH., in 2007, had reported the reduction of 2,3-

dihydro-1H-1-indanone oxime 15 using alumino-nickel 

catalyst in the presence of sodium hydroxide solution and 

ethyl alcohol to isolate 2 (yield: 80.11%, as oily mass). In 

another experiment, 9 was treated with oxammonium 

hydrochloride in the presence of sodium hydroxide 

solution and ethyl alcohol. Later to the reaction mixture 

added alumino-nickel catalyst and worked up to isolate the 

hydrochloride of 2 with a melting point of 208.4-209.5oC 

(yield: 76.68%, purity: 98.64% by HPLC, as white 

crystals). It was treated with 8 in the presence of sodium 

hydroxide solution and toluene to isolate the racemic 

Rasagiline base (yield: 79.07%, purity: 93.08% by HPLC, 

as brown oily mass). In another instance, 15 was dissolved 

in ethyl alcohol and treated with sodium hydroxide 

solution. To the reaction mixture added alumino-nickel 

catalyst for the reduction and later added 8 to isolate the 

racemic Rasagiline base (yield: 64.89%, purity: 90.45% by 

HPLC, as brown oily mass). In another example, 9 was 

treated with oxammonium hydrochloride in the presence 

of sodium hydroxide solution and ethyl alcohol. To it, 

added alumino-nickel catalyst for the reduction and then 

added 8 to isolate racemic Rasagiline base (yield: 62.3%, 

purity: 92.03% by HPLC, as pale brown oily mass). In a 

few separate experiments, racemic Rasagiline base was 

treated with L-tartarate in isopropyl alcohol to get the 

crude solid, which was recrystallized in isopropyl alcohol 

to isolate R-di-(Rasagiline) tartarate with the melting 

points in the range of 174.2-177oC (yield range: 20-26%, 

purity range: 97.46-98.54% by HPLC, as white puffy 

crystals). It was treated with methanesulfonic acid in 

isopropyl alcohol to isolate 1 with a melting point of 155-

155.8oC (purity: 99.85% by HPLC, as white crystals) [16]. 

Feng Q., in 2007, had demonstrated a simple process to 

isolate the reacemic Rasagiline base by reacting 9 in ethyl 

alcohol with 6 in the presence of sodium 

borohydride/palladium-carbon. Around six illustrations 

were reported with a slight modulated reaction conditions 

and isolation procedures with good yield (60.19-73.10%) 

[17]. 

N21 NH22

NH2

20
    



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 135  

Zongxuan S, et al., in 2008, had illustrated the 

condensation of 9 in isopropyl acetate with S-(-)-1-

phenylethylamine 20 in the presence of p-toluene-sulfonic 

acid monohydrate to form (1Z)-N-phenyl-2,3-dihydro-1H-

inden-1-imine 21 (82.5%). It was reduced under the impact 

of Raney-nickel in isopropyl acetate to isolate N-phenyl-

2,3-dihydro-1H-inden-1-amine 22 (yield: 88%). It was 

dissolved in tetrahydrofuran and treated with phosphorus 

pentachloride in the presence of triethylamine and then 

treated with oxammonium hydrochloride to isolate R-

isomer of 2 (as free base or its hydrochloride salt, yield: 

70-90%). Hydrochloride salt of 2 in acetonitrile was 

treated with 3 in the presence of potassium carbonate 

followed by the addition of methanesulfonic acid in diethyl 

ether to obtain 1 with a melting point of 156-158oC [18].  

Bosch ILJ, et al., in 2009, had reported a few reactions of 

R-isomer of 2 in toluene with 8 in the presence of sodium 

hydroxide solution to get R-Rasagiline base (yield: 67.82-

72.49%). It was treated with methanesulfonic acid in 

toluene or acetonitrile to isolate the crude 1 (yield: 85.54-

97.39%, purity: 79.65-93.32% by HPLC). Furthermore, a 

double recrystallization of crude 1 was done from 

acetonitrile and then the solid obtained was suspended in 

acetonitrile/water mixture to get 1 (overall yield: 22-33%, 

purity: 99-100% by HPLC). They had reported the 

recrystallization of 1 in isopropyl alcohol, but the final 

product and the filtrate had isopropyl mesylate traces as an 

impurity (by GC analysis) [19].   

Frenkel A, et al., in 2009, had demonstrated the isolation 

of crystalline solid R-Rasagiline base (yield: 70-90%) from 

its mesylate or tartarate by a few methods like splitting, 

extraction, water crystallization, melt crystallization, 

quenching to water, reverse quenching, seeding 

crystallization etc. Under the usual conditions, R-

Rasagiline base would be used in its crude form as an oily 

liquid. The work had reported the isolation of the solid 

form of R-Rasagiline base by various crystallization 

approaches with a melting point of 15-20oC (isolated from 

toluene), 38.2-38.4oC (isolated from water), 39.0-39.2oC 

(isolated from isopropyl alcohol), 40.8oC (isolated from 

isopropyl alcohol/water by seeded emulsion) and 41.3oC 

(isolated from isopropyl alcohol/water by seeding 

crystallization) [20-22]. 

Gore V, et al., in 2009, had disclosed a process to get 

enantiomerically pure R-isomer of 2 by treating racemic 2 

with 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid 

monohydrate in methyl alcohol to isolate the crude salt. It 

was dissolved in aqueous methyl alcohol and crystallized 

to isolate the salt. Pure R-isomer of 2 (yield: 40-42%, 

chiral purity: 96-97% by HPLC, as light green oily liquid) 

was isolated by salt breaking method in the presence of 

sodium carbonate solution and extracting the free base to 

dichloromethane [23]. The reported work was much 

superior to the past disclosed resolving techniques [12,24].  

Frenkel A & Koltai T., in 2009, had illustrated a process 

to manufacture of Rasagiline tannate. Rasagiline base was 

treated with tannic acid solution to obtain the first mixture. 

A partial removal of the liquid from the first mixture and 

the addition of a polar water soluble solvent (ethyl alcohol) 

had resulted in the formation of second mixture. 

Furthermore, liquid/solvent was removed completely at 

ambient temperature to isolate the tannate salt. The 

isolated Rasagiline tannate had the water content of below 

10% and the Rasagiline content was got varied around in 

the range of 3-64%. The work had disclosed the cleavage 

of 1 to isolate Rasagiline base as an oily mass and its 

crystallization to isolate in the solid form with a melting 

point of 39-39.3oC. It was then treated with tannic acid 

solution in various methods to isolate the tannate salt. An 

improved Rasagiline tannate salt formation was observed 

in polar solvents than in non-polar solvents (ethyl acetate 

and hexane) [25].  

Caigu H & Huimin H., in 2009, had reported the process 

to isolate the crystal form-I of 1. It was prepared by taking 

1 in (ethyl acetate/ethyl alcohol) or (acetone/ethyl alcohol) 

or acetonitrile or isopropyl alcohol. The isolated solid had 

exhibited a prominent DSC endotherm at 157-157.5oC 

[26]. Stephen BDW., in 2009, had reported the synthetic 

pathway to isolate the crystal form-I of 1. The work had 

employed various solvents to dissolve 1 and isolate the 

crystal form-I at 25-70oC [27]. Patil NS, et al., in 2009, 

had demonstrated a process to prepare 1 with 90 volume-

percent of the particles (D-90) with a size of about (600-

1500 microns) and (255-1500 microns). It was prepared 

from 1 or Rasagiline base using the suitable solvents [28].  

S

O

O

Cl

N
O

O
23

NH

SO
O

N

O

O

24

N

SO
O

N

O

O

25



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 136  

Qiandong L, et al., in 2009, had demonstrated the 

condensation of R-isomer of 2 in dichloromethane with O-

nitro-benzene-sulfonyl chloride 23 in the presence of 

triethylamine to isolate R-N-(2-nitro) benzenesulfonyl-1-

indenamine 24 (yield: 95%, as white solid). It was 

dissolved in toluene and treated with 3 in the presence of 

sodium hydroxide and catalytic amount of 

tetrabutylammonium bromide to get R-N-propargyl-N-(2-

nitro)-benzenesulfonyl-1-indenamine 25 (yield: 81%, as 

pale yellow solid). N,N-dimethylformamide, lithium 

hydroxide monohydrate and mercapto-propionic acid were 

added to 25 to isolate R-Rasagiline base (yield: 96%, as 

yellow oily liquid). The work had also reported the use of 

racemic 2 for the above steps to get racemic Rasagiline 

base, which was treated with L-tartaric acid in isopropyl 

alcohol to isolate the salt. It was dissociated further to 

isolate the R-Rasagiline base (as yellow brown oil) [29].  

Huang C & He H, in 2009, had disclosed the preparation 

of form-I of 1 from various solvents like isopropyl alcohol, 

ethyl alcohol, acetone, ethyl acetate and acetonitrile. The 

crystal form-I had showed the characteristic endothermic 

peak at about 157.07oC [30]. 

Cherukupally P, et al., in 2010, had illustrated the reaction 

of 9 in methyl alcohol with 6 to isolate hydrochloride salt 

of (1Z)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-imine 

16. It was then reduced using sodium borohydride in 

methyl alcohol to get the crude racemic Rasagiline base. It 

was treated with isopropyl alcohol/HCl (18%) to get the 

racemic Rasagiline hydrochloride. Moreover, the salt 

cleavage had resulted in the formation of Rasagiline base. 

The work also had reported the use of a few suitable 

reducing agents like Raney nickel, palladium on carbon, 

and platinum dioxide; lithium aluminium hydride; sodium 

borohydride; sodium cyanoborohydride; sodium 

borohydride in acidic conditions; and sodium bis(2-

methoxyethoxy)-aluminum hydride (vitride®) to isolate 16 

in reasonably high yields. A few suitable chiral resolving 

agents were used like L-(+)-tartaric acid and (-)-di-p-

toluoyltartaric acid (DPTTA) to isolate the required R-

isomer. With the use of these reagents, enantiomerically 

pure salts of Rasagiline (hydrochloride/tartarate/mesylate) 

were prepared with good yields. Furthermore, the work 

provides a process for the preparation of 1 having 

D90 below 6 μm. It was done by adding the solution of 1 in 

isopropyl alcohol to chilled methyl-t-butyl ether. The work 

involved the isolation of Rasagiline & its salts which are 

significantly free from the critical impurities like N,N-

di(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine 4, N-

(prop-2-en-1-yl)-2,3-dihydro-1H-inden-1-amine 17, N-

propyl-2,3-dihydro-1H-inden-1-amine 18 & 3-(prop-2-yn-

1-ylamino)-2,3-dihydro-1H-inden-1-one 19 [31].  

O
OH

26

S

O

NH2
30

NH
S O

31

N
S O

32

Br

27
NH28 OH

OH

O

O

NH

Br

Br

29

Br

NH NH

Br

33 34

Marras G, et al., in 2010, had disclosed a multi-step 

process starting from (±)-2, 3-dihydro-lH-indene-l-

carboxylic acid 26 to isolate R-Rasagiline base (as light 

green oily mass). The process had involved a series of 

reaction steps like Curtius rearrangement, resolution, 

hydrolysis, de-protection etc to isolate the intended 

product [32]. 

Allegrini P, et al., in 2010, had illustrated the 

condensation of 6 and 9 in the presence of sodium 

borohydride in tetrahydrofuran to isolate the racemic 

Rasagiline base (yield: 91%). It was treated with L-(+)-

tartaric acid in ethyl alcohol to get R-Rasagiline tartarate. 

It was cleaved under nitrogen atmosphere using sodium 

bicarbonate solution and ethyl acetate to isolate R-



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 137  

Rasagiline base (as an oily liquid). It was taken in 

isopropyl alcohol and treated with methanesulfonic acid to 

isolate 1 (yield: 89% from its tartarate salt). The work was 

extended further to provide the procedure to isolate the 

crystalline form of R-Rasagiline base with a melting of 40-

41oC [33]. 

Phull MS, et al., in 2010, had reported a multi-step 

process to isolate 1. In an example, 9 was reacted with 

allyl bromide 27 in the presence of potassium carbonate in 

acetonitrile and then treated with oxalic acid to obtain R-(-

)-N-allyl-1-aminoindan oxalate 28. It was de-oxalated and 

then brominated (by bromine) in dichloromethane to 

isolate R-(-)-N-(2,3-dibromo-propyl)-1-aminoindan 29. It 

was hydrolyzed using potassium hydroxide solution in 

ethyl alcohol to isolate R-Rasagiline oxalate. Under the 

similar conditions, racemic 29 was synthesized and 

hydrolyzed. It was then treated with L-tartaric acid to 

isolate the crude solid. It was then de-tartarated by treating 

with sodium hydroxide solution and mesylated by the 

addition of methanesulfonic acid in isopropyl alcohol to 

obtain 1 (purity: 99.8%, chiral purity: 99.5%). The 

resolving process can be adapted to racemic 28 using L-

tartaric acid or it can be effectively implemented to 

racemic 29 using L-tartaric acid. The work had provided 

an improved process by eliminating the drawbacks of past 

disclosures [34].  

Stahl HP., in 2010, had demonstrated the preparation, 

solubility profile, and hygroscopicity details of two new 

salts of Rasagiline. Rasagiline base was taken in isopropyl 

alcohol and ethanedisulfonic acid was added to isolate 

Rasagiline edisilate with a melting point of 201oC (yield: 

56.3%). Under the similar conditions, Rasagiline base was 

treated with oxalic acid in isopropyl alcohol to obtain 

Rasagiline oxalate with a melting point of 204oC (yield: 

93.1%) [35]. 

Frenkel A, et al., in 2010, had reported the isolation of 

mono-Rasagiline citrate, di-Rasagiline citrate or tri-

Rasagiline citrate or a mixture of all them. These salts or 

salt mixtures were prepared by treating Rasagiline base 

(solid) with citric acid in ethyl alcohol or a few other 

solvents/water [36].  

Stephen BDW, et al., in 2010, had illustrated a few more 

Rasagiline salts such as tartrate  with a melting point of 

176.2-177.3oC, maleate with a melting point of 87.2-

87.8oC, sulphate with a melting point of 159.4-161.1oC, 

hydrochloride with a melting point of 177.0-180.0oC, 

tosylate with a melting point of 129.3-129.9oC, fumarate 

with a melting point of 125.4-126.2oC, phosphate with a 

melting point of 109.5-110.4oC, acetate with a melting 

point of 69.2-69.7oC, besylate, tannate, benzoate, 

galactarate, gluconate, glucuronate, succinate, hetartarate 

etc from Rasagiline base using various suitable 

solvents/water. Some of those salts were isolated in their 

crystalline forms (form I/II) and a few salts in their 

amorphous form [37].  

Thomas T, et al., in 2011, had reported the preparation and 

advantages of a few salts of Rasagiline such as gluconate, 

L-aspartate, citrate, DL-lactate, saccharinate, docusate, 

lauryl sulphate, 4-dodecylbenzenesulfonate, linoleate, 

pentanoate, propanoate, acetate, decanoate, octanoate, 

hexanoate and oleate. These salts were prepared from 

Rasagiline base using appropriate solvents [38]. 

Patil NS, et al., in 2011, had demonstrated the isolation of 

a few Rasagiline salts. The salts reported are maleate 

(form-II), mandelate (form-I) and salicylate (form-I), 

surprisingly these salts had good purity and had exhibited 

an adequate stability, good flowability and a good 

dissolution properties [39]. 

Dongwei C, et al., in 2011, had illustrated a multi-step 

process to isolate 1. The reaction of 9 with t-butyl-

sulfinamide 30 was carried out under the catalytic impact 

of isopropyl titanate in tetrahydrofuran to get N-(2,3-

dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide 

31 (yield: 59%). It was dissolved in dimethyl formamide 

and reacted with sodium-t-butoxide. To the reaction mass, 

7 was added to isolate N-(2,3-dihydro-1H-inden-1-yl)-2-

methyl-N-(prop-2-yn-1-yl)propane-2-sulfinamide 32 

(yield: 51% from 9). The solution of methanesulfonic acid 

in diethyl ether was added to the solution of 32 in methyl 

alcohol to isolate the enantiomerically pure 1 with a 

melting point of 156-158oC (yield: 46% from 9, as white 

crystals, isolated from methyl-t-butyl ether) [40]. 

Chi-Hsiang Y & Tsung-Ting C., in 2011, had reported the 

condensation of 9 with 6 in methyl-t-butyl ether using p-

toluene sulfonic acid to form the intermediate 16. It was 

effectively reduced using 20% di-isobutyl-aluminum-

hydride (DIBAL-H) in hexane to isolate the racemic 

Rasagiline base (yield: 81%). It was treated with S-(+)-

mandelic acid in methyl-t-butyl ether to isolate R-

Rasagiline mandelate (yield: 45%). De-salting it with 2% 

sodium hydroxide solution gave R-Rasagiline base (yield: 

90%). It was treated with methanesulfonic acid in 

isopropyl alcohol to isolate 1 (yield: 80%) [41]. 

Gore V, et al., in 2011, had illustrated the condensation of 

R-isomer of 2 with 8 under the influence of 1,8-

diazabicyclo-[5,4,0]-undec-7-ene (DBU) in 

tetrahydrofuran to get R-Rasagiline base (yield: 80-82%, 



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 138  

purity: 64.33% by HPLC, as yellow oily mass). It was 

treated with methanesulfonic acid in isopropyl alcohol to 

isolate 1 (yield: 47%, purity: 99.84%, chiral purity: 100% 

by HPLC) [42]. 

Thanedar AA, et al., in 2011, had demonstrated a 

comparative example to condense racemic 2 in acetonitrile 

with 7 in the presence of  potassium carbonate to isolate 

racemic Rasagiline base (yield: 101%, purity: 72.33% by 

HPLC, as oily residue). It was done as per the previous 

disclosure [10]. In another example, 9 in ethyl alcohol was 

reacted with 6 in the presence of titanium (IV) iso-

propoxide to form the respective titanium complex. It was 

reduced by sodium borohydride and performed acid-base 

isolation to get racemic Rasagiline base (yield: 22.57%, 

purity: 98% by HPLC). It was resolved using L-(+)-tartaric 

acid in isopropyl alcohol to isolate the crude salt. It was 

recrystallized from methyl alcohol to isolate R-Rasagiline 

tartarate (recovery: 80%, purity: 99.89% by HPLC). It was 

de-salted and treated with methanesulfonic acid in acetone 

to isolate 1 (yield: 72.12%, purity: 99.97% by HPLC). A 

direct conversion process of tartarate salt to 1 (yield: 

88.14%, purity: 99.5%, chiral purity: 99.9% by HPLC) 

was also reported [43]. 

Selic L., in 2011, had disclosed the preparation of a few 

salts of Rasagiline and those are exclusively used to 

resolve racemic Rasagiline base. The major salts reported 

are Rasagiline-L-mandelate, Rasagiline-D-mandelate, 

Rasagiline-R-mandelate (yield: 33%, with a melting point 

of 107-111oC), R-Rasagiline-(+)-camphor-10-sulfonate 

(yield: 27%, with a melting point of 167-170oC), 

Rasagiline orotate, Rasagiline cinnamate, Rasagiline-1-

hydroxy-2-naftoate, Rasagiline fumarate, Rasagiline 

benzoate and Rasagiline-(-)-camphor-10-sulfonate. The 

work also had disclosed the recrystallization methods of 

those salts along with an efficient analysis method [44].  

Zope SS, et al., in 2011, had demonstrated the synthesis of 

some Rasagiline salts like, R-Rasagiline phosphate (purity: 

99.96%), R-Rasagiline benzoate (yield: 78%, purity: 

99.94%), R-Rasagiline mandelate (yield: 61%, purity: 

99.89%) and R-Rasagiline oxalate (purity: 99.9%) from R-

Rasagiline free base in isopropyl alcohol [45]. 

Sun J, et al., in 2011, had reported a method to prepare R-

Rasagiline base starting from racemic 2 as the raw material 

through enzyme-catalyzed asymmetric acylation reaction, 

hydrolysis and N-propargylation reactions. The R-isomer 

of 2 in isopropyl ether was reacted with 8 in the presence 

of sodium carbonate solution to isolate the desired 

propargylated product (yield: 82.5%, as yellow oily liquid) 

[46]. 

Dwivedi SD, et al., in 2011, had illustrated the synthesis of 

many salts of Rasagiline from its base using the suitable 

solvents. The salts reported are R-Rasagiline 

hydrobromide form-I, amorphous Rasagiline 

hydrobromide, R-Rasagiline hydrogen phosphate, 1 from 

R-rasagiline hydrobromide form-I, form-I of 1, R-

Rasagiline 1,2-edisylate form-II, crystalline R-Rasagiline-

2-napsylate, R-Rasagiline-1,5-dinapsylate form-I, R-

Rasagiline 1,5-dinapsylate form-II, crystalline R-

Rasagiline-l-napsylatate, R-Rasagiline ascorbate, 

amorphous Rasagiline ascorbate [47]. 

Sathe DG, et al., in 2011, had demonstrated the reaction of 

R-(-)-isomer of 2 hydrochloride with 8 in the presence of 

sodium hydroxide solution and tetra-butyl-ammonium-

bromide to get the crude R-Rasagiline base (yield: 60%, as 

an oily mass). It was subjected to column chromatography 

to isolate R-Rasagiline base (recovery: 90%). The un-

reacted R-(-)-isomer of 2 was recovered by the basification 

and extraction processes. R-Rasagiline base was treated 

with methanesulfonic acid in isopropyl alcohol to isolate 1 

(yield: 83%). The work was extended further to provide 

the preparation methods of Rasagiline hydrochloride, 

form-I and form-II, Rasagiline hydrobromide, Rasagiline 

palmitate. Furthermore, the work reported the route to 

synthesize and isolate the impurities like 33 (impurity A) 

and 34 (impurity B) [48]. 

 



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 139  

 

Elffrink WWJ, in 2011, had disclosed the techniques to 

synthesize a few crystallographic forms of Rasagiline 

hydrochloride like form-I (as per the past disclosures), 

form-II and form-III (by the use of an inert solvent for a 

sufficient time to attain the conversion) [49].  

Bohumil D., in 2012, had illustrated the resolution of 

racemic 2 in methanol using L-(+)-aspartic acid, L-(-)-

malic acid and (2R, 3R)-tartaric acid. The work had 

reported the conversion of S-isomer of 2 to its R-isomer 

(yield: 94%, purity: 96% by HPLC) in the presence of 

potassium-tert-butoxide in dimethyl sulfoxide. It also 

extends to report the condensation of R-isomer of 2 

hydrochloride with 3 in the presence of sodium hydroxide 

solution under the toluene medium to form Rasagiline base 

(not isolated). To the Rasagiline base dissolved in toluene, 

added methanesulfonic acid in isopropyl alcohol to isolate 

1 (purity: 99.86%, chiral purity: 100%, by HPLC) [50].  

Liu G, et al, in 2012, had reported the condensation of R-

isomer of 2 with methyl trifluoroacetate 35 in methyl 

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

2,2,2-trifluoroacetamide 38 (yield: 96%, purity: 99.5% by 

HPLC). Similarly, ethyl trifluoroacetate 36 in ethyl alcohol 

was used to isolate 38 (yield: 98%, purity: 99.7% by 

HPLC). Additionally, butyl-trifluoroacetate 37 in pentyl 

alcohol or tetrahydrofuran was used to get 38 (yield: 94%, 

purity: 99.2% by HPLC). In the next step, 38 was treated 

with 7 in the presence of N,N-dimethylformamide and 

sodium hydroxide solution to obtain N-[(1R)-2,3-dihydro-

1H-inden-1-yl]-2,2,2-trifluoro-N-(prop-2-yn-1-

yl)acetamide 39 (yield: 86%, purity: 99.1% by HPLC). A 

slight process modification was done to condense 3 to with 

38 to obtain 39 (yield: 90%, purity: 99.7% by HPLC). A 

few different reagents and solvents were used to condense 

3 or 7 with 38 to isolate 39 with good optical purity. 

Hydrolysis of 39 under the suitable alkaline conditions had 

resulted in the formation of R-Rasagiline base (yield: 86-

96%, purity: 99.8-99.3%). It was treated with 

methanesulfonic acid in diethyl ether to get 1 (yield: 82%, 

purity: 99.3%) [51].  

Oemer R, et al, in 2012, had demonstrated a high yield 

method for the synthesis of 1 by the alkylation of 39. The 

trifluoroacetyl protection had enabled to carry out an 

alkylation of 38 with a high yield and purity under very 

mild conditions with a wide range of reaction conditions 

and reagent selection. R-isomer of 2 hydrochloride was 

treated with trifluoroacetic anhydride 40 in the presence of 

pyridine and dichloromethane to isolate 38 (yield: 95%, 

purity: 99.5% by HPLC). It was alkylated with 3 in the 

presence of cesium carbonate in acetonitrile to isolate 39 

(purity: 97.8% by HPLC) and then hydrolyzed in the 

presence of potassium hydroxide solution and methyl 

alcohol to get R-Rasagiline base (purity: 99.5% by HPLC). 

It was taken in isopropyl alcohol and added 

methanesulfonic acid to get 1 (yield: 88%, purity: 100% by 

HPLC, as white crystals) [52]. 

Yao Q & Chen Z, in 2012, had illustrated the condensation 

of 9 with 6 in the presence of p-toluenesulfonic acid in 

methyl-t-butyl ether to form 16. It was dissolved in-situ in 

toluene and added 20% di-isobutylaluminum hydride 

solution (DIBAL-H dissolved in n-hexane) and worked up 

to isolate racemic Rasagiline base (yield: 81%). It was 

resolved by converting to its mandelate salt (yield: 45%) to 

isolate the required R-isomer. It was subjected to de-

saltation (yield: 90%) using sodium hydroxide solution 

and then treated with methanesulfonic acid in isopropyl 

alcohol to obtain 1 (yield: 80%) [53]. 

Tang L, et al., in 2012, had reported the treatment of 15 in 

aqueous ethyl alcohol with aluminium-amalgum to isolate 

racemic 2 (purity: 98.9-99.9%). It was condensed with 8 in 

the presence of sodium hydroxide solution and 

dichloromethane to form racemic Rasagiline base. It was 

resolved by the formation of tartarate salt in isopropyl 

alcohol to isolate R-Rasagiline tartarate with a melting 



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 140  

point of 174.9-176.3oC (yield: 41.05%). It was dissolved in 

isopropyl alcohol and treated with methanesulfonic acid to 

obtain 1 with a melting point of 150.1-151oC (yield: 81%) 

[54].  

Nagarajan K, et al., in 2012, had demonstrated a process 

to isolate 1 with a particle size of about 255-590 microns. 

It was achieved by the crystallization from isopropyl 

alcohol and the disclosed method was devoid of routine 

comminution techniques to control the particle size of 1 

[55]. 

Dwivedi SD, et al., in 2011, had illustrated the process to 

isolate R-Rasagiline besylate form-I with the larger particle 

size by treating Rasagiline base with benzene sulfonic acid 

solution in ethyl acetate. Similarly, a few other salts were 

also prepared like R-Rasagiline hydrobromide form-I and 

its larger particle size, amorphous Rasagiline 

hydrobromide, R-Rasagiline hydrogen phosphate form-I 

and form-I of 1. The reaction of 9 in methyl alcohol with 

hydroxylamine hydrochloride was carried out in the 

presence of sodium hydroxide solution to obtain 15. It was 

reduced under the catalytic impact of Raney-nickel (with 5 

Kg of hydrogen pressure) in the presence of ammoniacal 

methyl alcohol to get racemic 2. It was treated with 7 in 

the presence of potassium carbonate and sodium hydroxide 

using the solvent dimethyl formamide to isolate the 

racemic Rasagiline base (as yellow oil). The isolated base 

was resolved using L-(+)-tartaric acid and desalted to 

isolate R-Rasagiline base (as oil) and then converted to 

required salt forms [56].  

Zhang R, et al., in 2012, had disclosed the condensation of 

R-isomer of 2 in acetonitrile with propargyl 

methanesulfonate 44 to isolate 1 with a melting point of 

156-158oC (yield: 97.8%). The isolation of 1 in different 

scales as above was reported via one-pot processes (yield: 

85-92%) along with a few comparative examples as per 

the past disclosures [57]. 

Bahar E, et al., 2012, had demonstrated the synthesis and 

applications of deuterated Rasagiline, its salts. The work 

was primarily focused on the varied metabolic profile of 

deuterated forms of Rasagiline than the protonated forms. 

To substantiate it, phase-I bio-trasformations of deuterated 

Rasagiline was conducted with encouraging results [58].  

Ulanenko K, et al., in 2013, had reported the synthesis of 

2-(2-((2, 3-dihydro-li/-inden-l-yl)(prop-2-ynyl)amino)-2-

oxoethyl)-2-hydroxysucckiic acid 42 from citric acid 41. 

In the first step, 41 was esterified to form trimethyl citrate. 

It was then converted to 1, 2-dimethyl citrate by a selective 

stearically controlled saponification. In the next step, an 

amidation reaction was conducted between R-Rasagiline 

base and 1, 2-dimethyl citramide and finally the esters 

were hydrolyzed to isolate 42 (yield: 3.5%) [59].  

Santosh VP, et al., in 2013, had reported the condensation 

of R-(-)-isomer of 2 hydrochloride in acetonitrile with 7 in 

the presence of potassium carbonate to isolate crude base. 

It was purified by the selective pH adjustment and 

selective extraction to suitable solvents to isolate R-

Rasagiline base (purity: 99.82% by HPLC, as oily mass). It 

was treated with methanesulfonic acid in isopropyl alcohol 

to obtain 1 (purity: 99.99% by HPLC). An optional 

isolation of free base was reported by converting in-situ to 

1 with good purity. This work avoids the tedious and time-

consuming column chromatographic purification method 

& the solvent recrystallization techniques to get pure free 

base, instead had incorporated a simple workup techniques 

to get the R-Rasagiline base with high purity. [60]. 

Gade SR, et al., in 2013, had demonstrated the treatment 

of Rasagiline base with L-(+)-tartaric acid in methyl 

alcohol to isolate Rasagiline hemi-tartarate (yield: 70-75%, 

purity: 99.91-99.98% by HPLC) [61]. 

 



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 141  

Sun Y, et al., in 2014, had demonstrated a one-pot 

synthetic process to condense R-(-)-isomer of 2 in 

acetonitrile or N,N-dimethyl formamide with  propargyl-p-

toluenesulfonate 43 or 44 in the presence of sodium 

carbonate or potassium carbonate or triethylamine to form 

an intermediate. It was not isolated, but immediately 

treated with methanesulfonic acid to isolate the crude 

solid. It was recrystallized in isopropyl alcohol to isolate 1 

with a melting point of 156-157oC (yield: approximately 

40-50%, purity: more than 99.5% by HPLC). The work 

was extended further to isolate a few impurities like prop-

2-yn-1-yl (1R)-2,3-dihydro-1H-inden-1-ylcarbamate 45 

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

2-yn-1-yl)carbamate 46 from the filtrate by the column 

chromatography technique [62]. 

Sun Y, et al., in 2014, had illustrated the isolation and 

analysis methods of 45, 46 and R-mesylate of 4. The 

LCMS data of isolated impurities are [M+H]+ 216.1 for 45, 

[M+H]+ 254.1 for 46 and [M+H]+ 210.1 for mesylate of 4 

[63].  

Prudic D, et al., in 2015 & 2016, had reported a process 

for the preparation of optically pure R-isomer of 2 by a 

diastereomeric resolution of racemic 2 using N-acetyl-L-

glutamic acid 47 as an effective resolving agent. The 

formation of diastereomeric salts of R-isomer of 2 with 47 

and their use in the synthesis of optically enriched 

Rasagiline base was also reported. Rasagiline base was 

treated with methanesulfonic acid in isopropyl alcohol to 

obtain 1 (yield: 76.6%, purity: 100% by HPLC). The 

reaction of 9 with hydroxylamine hydrochloride was 

carried out in ethyl alcohol to get 15 (yield: 91.6%). It was 

reduced by Raney-nickel in the presence of ammonia 

enriched methyl alcohol to isolate racemic 2 (yield: 100%) 

[64, 65]. 

Frenkel A, et al., in 2015, had reported the synthesis of 19 

from N-(2,3-dihydro-1H-inden-1-yl)acetamide 48. 

Impurity 19 was formed during the production of 1 under 

certain specific conditions. The work was extended further 

to contribute a commercial process to get 1 with very low 

content of 19. Racemic 2 was treated with 8 in the 

presence of sodium hydroxide solution to isolate racemic 

Rasagiline base. It was treated with L-tartaric acid in 

isopropyl alcohol to isolate R-Rasagiline tartarate, it was 

then de-salted and treated further with methane sulfonic 

acid to isolate 1 (with around 0.01-0.02% of 19 content) [66].  

Chen J, et al., in 2019, had demonstrated the reaction of 

R-(-)-isomer of 2 with Propynoic acid 49 in 

dichloromethane under the presence of suitable acid amine 

coupling agents like dicyclohexylcarbazone/ 4-

dimethylaminopyridine to get N-[(1R)-2,3-dihydro-1H-

inden-1-yl]but-3-ynamide 50 (yield: 97.7%, purity: 

96.76% by HPLC). Similarly, the use of 1-

hydroxybenzotriazole/ 1-(3-dimethylaminopropyl)-3-

ethylcarbodiimide hydrochloride in tetrahydrofuran gave 

50 (yield: 95.2%, purity: 96.59% by HPLC). The use of 

(azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-

hexafluorophosphate/ di-isopropylethylamine in 2-

methyltetrahydrofuran had resulted in the formation of 50 

(yield: 96.8%, purity: 96.84% by HPLC). It was dissolved 

in toluene/xylene/benzene and treated with 

diphenylsilane/triphenylsilane/diphenylmethylsilane and 

di-o-chlorophenylboronic acid/ bis-fluorophenylboronic 

acid to isolate Rasagiline base (yield: 59.4-60.7%, purity: 

99.72-99.77% by HPLC). It was diluted in isopropyl 

alcohol and treated with methanesulfonic acid to obtain 1 

(yield: 58.5%, purity: 99.89% by HPLC) [67].   

Li J, et al., in 2020, had reported a one-pot synthetic 

procedure to isolate Rasagiline base by the condensation of 



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 142  

9 with 6 in the presence of a suitable dehydrating agent/s 

(sodium borohydride, glacial acetic acid and tetra-

isopropyl titanate) in tetrahydrofuran to isolate racemic 

Rasagiline base (yield: 93.6%, purity: 95.67% by HPLC, 

as red-brown oily liquid). It was resolved by the use of L-

(+)-tartaric acid to get R-Rasagiline tartarate (yield: 39%, 

purity: 99.46% by HPLC, as off-while solid). It was de-

salted and treated with methanesulfonic acid in isopropyl 

alcohol to get 1 (yield: 87.6%, purity: 99.80% by HPLC) 

[68].  

Ma Y, et al., in 2020, had demonstrated the condensation 

of R-(-)-isomer of 2 with 3 in the presence of N,N-

diisopropylethylamine in acetonitrile to isolate R-

Rasagiline base (yield: 45.3-58%, purity: 91.4-97.54% by 

HPLC). It was dissolved in isopropyl alcohol and added 

methanesulfonic acid to isolate 1 (yield: 83.1%, purity: 

99.3% by HPLC). The work had even covered the process 

to recover the un-reacted 2 from the filtrate (recovery: 

32%, purity: 81% by HPLC) [69]. 

Ma Y, et al., in 2021, had illustrated the synthesis of a few 

critical genotoxic impurities like (1R)-N-(2-chloroprop-2-

en-1-yl)-2,3-dihydro-1H-inden-1-amine 51 (purity: 84.6% 

by HPLC, as light yellow oil), (1R)-N-[(2E)-3-chloroprop-

2-en-1-yl]-2,3-dihydro-1H-inden-1-amine 52 (yield: 

89.3% by HPLC, as yellow oil), (1R)-N-[(2Z)-3-

chloroprop-2-en-1-yl]-2,3-dihydro-1H-inden-1-amine 53 

(purity: 88.4% by HPLC, as yellow oil), (1R)-N-nitroso-N-

(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine 54 

(purity: 88-8.9% by HPLC, red-brown oil) and N-[(1R)-

2,3-dihydro-1H-inden-1-yl]-N-nitroso-2,3-dihydro-1H-

inden-1-amine 55 (purity: 75-79.8% by HPLC, as brown-

black oil). These are the process related impurities of 1, 

and are synthesized by the suitable reagents under the 

favorable reaction conditions. The work had even extended 

to provide the characterization details of impurities and 

their detection methods in the finished product [70,71]. 

Hu A, et al., in 2022, had demonstrated an electro-

reduction synthetic pathway (a green chemistry approach) 

to isolate racemic 2 hydrochloride. The reduction of 15 

under electrolytic conditions (alkaline) was performed in 

the presence of an organic solvent to obtain racemic 2 

hydrochloride with a melting point of 210-212oC (yield: 

90.6%, as a white solid) [72].   

Tang H, et al., in 2023, had reported the cyclization of 3-

phenylpropanoic acid 56 in the presence of 

trifluoromethanesulfonic acid and 

trifluoromethanesulfonic anhydride to isolate 15 (yield: 

86.84%, purity: 99.37% by HPLC). It was dissolved in 

tetrahydrofuran and treated with sodium 

triacetoxyborohydride and added the solution of 6 in 

tetrahydrofuran to obtain racemic Rasagiline 

hydrochloride (yield: 79%, purity: 99.67% by HPLC). It 

was de-salted and resolved using L-tartaric acid in methyl 

alcohol to isolate R-Rasagiline tartarate (yield: 34.38%, 

purity: 98.83%). It was treated with methanesulfonic acid 

in isopropyl alcohol to isolate 1 (yield: 94.97%, purity: 

100%, chiral purity: 100% by HPLC). The disclosed 

initiative was proved to be an industrially feasible process 

involving cyclization, reductive amination, resolution and 

salification using the readily available starting materials, 

simple reagents and solvents [73]. 

57

S

O

O

NH

N

O

O S

O

O
N

NO

O
58

Wu G, et al., in 2023, had illustrated the use of 9 as the 

starting material to obtain S-isomer of 13 (yield: 75.6-82%, 

purity: 98.3-98.6% by HPLC) in high purity through the 

asymmetric reduction of a chiral auxiliary and borane 

intermediate. It was dissolved in tetrahydrofuran and 

treated with 2-nitro-N-(prop-2-yn-1-

yl)benzenesulfonamide 57, triphenylphosphine and di-

isopropyl azodicarboxylate under the nitrogen atmosphere 

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

(prop-2-yn-1-yl)benzenesulfonamide 58 (yield: 81.5-85%, 

purity: 98-98.8% by HPLC). In this step, a chiral amine 

was constructed in a simple pathway and the amino group 

was protected by the nitro sulfonyl group. The reported 

work successfully avoids the formation of unwanted poly-

substituted byproducts. Intermediate 58 was dissolved in 

dimethylformamide and treated with lithium hydroxide 

solution. To the mixture, mercaptopropionic acid in 

dimethyl formamide was added drop-wise and worked-up 

by pH adjustment to obtain R-Rasagiline base (yield: 92%, 

97.5% by HPLC). Upon the use of lithium hydroxide 

solution in dimethyl acetamide and mercapto-acetic acid, 1 

was isolated with relatively good purity (yield: 84.4%, 

purity: 97.1% by HPLC). In another experiment, lithium-

bistrimethylsilylamide in N-methyl pyrrolidone and 

thioglycolic acid was used to isolate 1 in reasonably good 

purity (yield: 77%, purity: 95.8% by HPLC) [74]. 

Summary 

Numerous researchers (inventors) associated to various 

global organizations (assignees) had contributed to 

commercialize Rasagiline, its salts and crystallographic forms.  



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 143  

The information regarding the assignee of all the 

disclosures till date was revealed in Table 1. To the 

context, “Teva Pharma” leads under the category of 

publication of patents on various aspects of Rasagiline and 

its close related compounds. 

Table 1. List of organizations/institutions behind the disclosed work (patent/s applied by/assignee) 

Ref. No. Patent No. Applicant/s or Assignee Organization/s 

[4], 

[7]. 

US3513244A 

DE1443403A1 

Aspro Nicholas Ltd 

[5], 

[8],  

[9], 

[10]. 

US5453446A, 

EP0436492A2,  

WO9511016A1,  

US5532415A 

Teva Pharma [IL]; Technion Res & Dev foundation [IL] 

[6]. US3253037A Ciba Geigy Corp 

[11]. CN1031995C Orvet Bv [NL] 

[12]. WO02068376A1 ISP Finetech Ltd [IL] 

[13], 

[14], 

[15], [20], 

[25], 

[36], [66]. 

US 2006/0199974A1, 

US2007/112217A1, 

US7491847B2,  

EP2101569B1,  

US 7547806B2,  

US7855233B2 

EP2939669A1 

Teva Pharma [IL] 

[16]. CN101062897A Chongqing Pharm Res Inst Co [CN] 

[17]. CN1990455A Beijing D Venture Pharm Tech [CN] 

[18]. CN101260048A Suzhou Chireach Biomedical Tec [CN]  

[19], [27], 

[37]. 

US2009292141A1,  

WO2009118657A2 

US20100041920A1 

Medichem SA [ES] 

[21], [22], 

[53],  

[58], 

[59]. 

WO2009154777A,  

WO2009154782A1, 

WO2012058219A2,  

WO2012058219A2 

WO2013055684A1 

Teva Pharma [IL]; Teva Pharma [US] 

[23]. CA2723869A1 Generics UK Ltd [GB] 

[24]. EP0235590A2 Warner Lambert Co [US] 

[26]. CN101486655A Meide Jiangxi Biotechnology Co [CN] 

[28], 

[39]. 

WO2009122301A2 

WO2011080589A2 

Actavis Group Ptc Ehf [IS] 

 

[29]. CN101381314A Chengdu Healthcare Pharmaceuticals [CN] 

[30]. CN101486655A Meide Jiangxi Biotechnology Co [CN] 

[31]. WO2010059913A2 Dr. Reddys Lab Ltd [IN]; Dr. Reddys Lab Inc [US] 

[32]. WO2010049379A1 Chemo Iberica SA [ES] 

[33]. US2010029987A1 Dipharma Francis S R I [IT] 

[34]. EP2231582A1 Cipla Ltd [IN] 

[35], 

[38]. 

US2010234636A1 

WO2011003938A1 

Ratiopharm GMBH [DE] 

 

[40]. CN102010353A Winchem Science and Technology Co Ltd 

[41]. US2011218361A1 Everlight USA Inc [US] 

[42]. CN102203053A Generics UK Ltd 

[43], [45]. WO2011048612A2,  

WO2011095985A2 

Glenmark Generics Ltd [IN] 

[44]. WO2011064216A1 Lek Pharmaceuticals [SI] 

[46]. CN102154432A Bengbu BBCA Medicine Science Dev Co Ltd 



Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 144  

[47], [51]. WO2011121607A2,  

WO2012153349A2 

Cadila Healthcare Ltd [IN] 

[48]. EP2364967A2 USV Ltd [IN] 

[49], 

[50], 

[56]. 

WO2011012140A2 

WO2012116752A1 

WO2012153349A2 

Synthon BV [NL] 

[51]. CN102464589A Chiral Quest Suzhou Co Ltd 

[52]. WO2012096635A1 Fargem Farmasoetik Arastirma Gelistirme Merkezi Sanayi Ve Ticaret A S 

[TR] 

[53]. CN102476998A Taiwan Everlight Chemical Ind Corp 

[57]. CN102675122A Dongguan Daxin Biolog Technology Co Ltd 

[55], [50]. US20120321896A1,  

WO2013054346A2 

Alkem Lab Ltd [IN] 

[52]. CN102786422A Topharman Shanghai Co Ltd; Shanghai Inst Materia Medica; Shandong 

Topharman Medical Raw Material Co Ltd 

[61]. EP2610239A1 Dr. Reddys Lab Ltd [IN] 

[62], [63]. CN103804200A,  

CN103864646A 

Changzhou No 4 Pharmaceutical Factory Co Ltd 

[64], [65]. WO2015070995A,  

WO2016116607A1 

Farma Grs D O O [SI] 

[67]. CN109180499A Shanghai Bocimed Pharmaceutical Co Ltd 

[68]. CN110776429A Qilu Pharmaceutical Co Ltd 

[69], [70], 

[71]. 

CN111333517A,  

CN113030283A,  

CN113045456A 

Shanghai Aobo Pharmtech Inc Ltd; Zhejiang Huahai Pharm Co Ltd 

[72]. CN114438531A Univ Hunan 

[73]. CN115838333A Jiangsu Szyy Pharmaceutical Res Institute Co Ltd 

[74]. CN115947675A Boji Medical Technology Co Ltd 

 

 CONCLUSION 

This work was primarily aimed to cover the disclosures in 

prior patents for the synthetic approaches on Rasagiline, its 

salts (in crystalline or amorphous forms) and a few 

impurities. Numerous patents were published at various 

patent trademark offices over the years covering many 

aspects of the drug, Rasagiline. To the context, the patents 

with attempts/explorings on the synthesis, impurity 

profiling, salt formation (in crystalline or amorphous form) 

of Rasagiline were considered, as retrieved from the web 

search tools/databases like Google Patents, USPTO 

(United States Patent and Trademark Office) and 

Espacenet (European Patent Office). This review work 

provides the essential information regarding the key 

starting material/s, reagents and solvents employed to 

obtain Rasagiline and its salts. The present review 

initiative can assist global researchers to venture further on 

the synthetic aspects and reaction optimization studies to 

isolate Rasagiline and its clinically acceptable salts. 

Racemization, recovery of S-isomer and its effective reuse 

are the key process bottle-necks either at the initial phase 

or at the end. An optimized process with the use of 

commercially viable starting material/s and the use of 

green solvents/ reagents under mild reaction conditions 

would favor the large scale manufacturing of Rasagiline 

and its stable salts. 

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Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 146  

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Sanjay S S                                                                                  Patents disclosed synthetic overview of Rasagiline 

Vol 2 | Issue 4 | Oct – Dec 2023                                                                          Indian J Pharm Drug Studies | 147  

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How to cite this article: Sanjay Sukumar Saralaya. 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):132-147.  

Funding: None             Conflict of Interest: None Stated  

 

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