Synthesis and characterization of impurities in rasagiline: A novel MAO-B inhibitor in Parkinson's disease therapy

Article abstract of DOI:10.14233/ajchem.2017.20505

Rasagiline (1) is indicated as adjunctive therapy and monotherapy for treatment of Parkinson's disease approved by the FDA. During the process development of rasagiline, few processes related impurities were observed along with the final API. These impurities were identified as indanol (2), indanamine (3), allyl (4), keto (7), other isomer (6) and chloro allyl (5,5a) impurities. The present work describes the synthesis of all these impurities and characterized by 1H NMR and Mass spectral analysis.

Full text of DOI:10.14233/ajchem.2017.20505

Asian Journal of Chemistry; Vol. 29, No. 6 (2017), 1357-1359
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20505
Synthesis and Characterization of Impurities in Rasagiline:
A Novel MAO-B Inhibitor in Parkinson’s Disease Therapy
1
2
N. MARUTHI RAJU1,2,*, J. MOSES BABU and B. VENKATESWARA RAO
1Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad-500 049, India
2Department of Organic Chemistry, Food, Drugs and Water, Andhra University, Visakhapatnam-530 003, India
*Corresponding author: E-mail: raju1001@gmail.com
Received: 10 January 2017;
Accepted: 31 March 2017;
Published online: 10 April 2017;
AJC-18354
Rasagiline (1) is indicated as adjunctive therapy and monotherapy for treatment of Parkinson’s disease approved by the FDA. During the
process development of rasagiline, few processes related impurities were observed along with the final API. These impurities were
identified as indanol (2), indanamine (3), allyl (4), keto (7), other isomer (6) and chloro allyl (5,5a) impurities. The present work describes
the synthesis of all these impurities and characterized by 1H NMR and Mass spectral analysis.
Keywords: 1-Indanone, N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine, Allyl bromide, Propargylamine hydrochloride.
Most of the impurities are chemicals only. Impurities are
INTRODUCTION
additional compounds those are not the drug substance [also
Among the various health problems, Parkinson’s disease
called as the active ingredient or the active pharmaceutical
are very critical one and eternal decadent disorder of the central
ingredient (API)], but rise while the synthesis, storage of the
nervous system that probably influence the motor system [1].
drug, extraction or purification. Knowing the source, prevail
Human cell having two forms of monoamine oxidase (MAO),
and quantification of impurities are critical to the preparation
which are MAO-A and MAO-B in the brain, but MAO-B is
of good quality drug substances.
far most frequent and is responsible for the disruption of
The consumption of medicines can lead to antagonistic
dopamine after its discharge into the synapse. Rasagiline
effects, which in the maximum of cases, are relevant to the entry
[IUPAC: R-(+)-N-propargyl-1-aminoindan (Fig. 1), [m.f.
of various impurities and substances that take place in the
C12H13N and m.w. 171.23] avoids the disruption of dopamine
remedy moreover the pharmacologically active ingredients into
by unreversible binding to MAO-B. So dopamine is respectively
the body. Impurities can have a strong antagonistic effect due
more available, somehow balancing for the decreased
to unacceptable toxicological and pharmacological action,
quantities made in the brains of humans with Parkinsons [2].
which can control over the certain effect of the medicine.Also
impurities can prevent the effect of the pharmaceutical pro-
perties of the drug substance [3].
The potential impurities in a drug substance (API) can
have a important impact on the safety and quality of the drug
substance. The percentage of impurities in any drug substance
HN
(R)
are represented as per its toxicological or biological data. It is
quite significant for “regulatory” aspect of drug substance
approval also to provide limits of “relevant impurities”. There-
fore, it is mandatory to study the impurities of any drug subs-
tance and prevail it while manufacturing of a drug substance.
Fig. 1. Chemical structure of rasagiline
As per the ICH guidelines, any impurity which is forming at
Drugs playing a prominent role in human life to fight
equal/more than 0.10 % with respect to the drug substance
various diseases. Unlike earlier days, most of the drugs currently
should be synthesized, identified and characterized exhaus-
are purely synthetically made. Unambiguously, the prepared
tively [4].
drugs contain different impurities like chemicals or microbes.

1358 Raju et al.
Asian J. Chem.
There are several methods to synthesize rasagiline. In all
Synthesis of 3-bromo-2,3-dihydro-1H-inden-1-one (9):
1-Indanone (8) (10 g, 0.0758 mol,1.0 eq) react with N-bromo-
succinimide (NBS) (13.8 g, 0.0758 mol 1.0 eq) in a catalyst
azobisisobutyronitrile (AIBN), was refluxed in CHCl3 (100
mL) solvent for 3 h. After completion of reaction the reaction
mixture was quenched with water, extracted with CHCl3, washed
with water, dried over sodium sulphate and concentrated under
methods, some common process related impurities like
1-indanol, 1-indanamine, allyl impurity, chloro allyl impurity,
S-isomer and keto impurity. 1-Indanol is commercially
available; remaining impurities synthesized and characterized
by 1H NMR and Mass spectral analysis.
EXPERIMENTAL
1
reduced pressure to obtain the 11 g compound 9. H NMR
All reactions were carried out in oven-dried glassware
(120 °C) under an atmosphere of nitrogen.Acetonitrile, chloro-
form and acetone were purchased from Merck Inc. N-Bromo-
succinimide (NBS), azobisisobutyronitrile (AIBN), propargyl-
amine hydrochloride and Lindlar catalyst were purchased from
Aldrich Chemical Co.
Analytical thin layer chromatography (TLC) was perfor-
med on precoated plates (silica gel 60 F-254), which were
purchased from Merck Inc. Purification by gravity column
chromatography was carried out by use of silicycle ultrapure
silica gel (particle size 40-63 µm, 230-400 mesh). Proton NMR
spectra were obtained on a Varian Mercury-400 (400 MHz)
spectrometer by use of chloroform-d (CDCl3) and DMSO-d6 as
solvents.
Synthesis of 2,3-dihydro-1H-inden-1-amine or 1-indan-
amine (3): To a stirred solution of 1-indanone (8) (5 g, 0.0379
mol, 1.0 eq), ammonium formate (14.31 g, 0.227 mol, 6.0 eq)
and Zn powder (6.9 g, 0.113 mol, 3.0 eq) in methanol (100
mL) was stirred under reflux. After completion of the reaction
the mixture was filtered through celite and the solvent was
removed by vacuum. The residue was treated with conc. HCl
solution (4 mL) and water (30 mL) and then extracted with
EtOAc (2 × 50 mL) to remove organic residues. The aqueous
phase was alkalized with ammonia solution to and extracted
with EtOAc (4 × 40 mL). The organic phase was washed with
brine, dried over sodium sulphate and the solvent removed
under vacuum resulted compound 3 2.75 g as 56 % yield
(80.18 % by HPLC). 1H NMR (400 MHz, CDCl3); δ 7.72 (d,
1H, Ar-H), 7.24 (m, 3H,Ar-H), 5.82 (d, 1H, NH), 5.58 (d, 1H,
NH), 4.90 (t, 1H, CH-NH2), 3.79 (d, 1H, Ar-CH2), 3.65 (d,
1H, Ar-CH2), 3.17 (m, 1H, CH2-CH), 2.89 (m,1H, CH2-CH).
Mass: m/z calcd. 133.09, found m/z 117.0 (M-NH2)+.
(400 MHz, CDCl3); δ 7.70 (dd, 3H,Ar-H), 7.47 (m, 1H,Ar-H),
5.59 (q, 1H, CH-Br), 3.34 (dd, 2H, CH2-CO), 3.03 (dd, 1H,
CH2-CO). Mass: m/z calcd. 211, found m/z 212 (M+1)+. HPLC
purity (%): 98.58.
Synthesis of 3-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-
inden-1-one or keto impurity (7): A solution of compound 9
(5 g, 0.0235 mol, 1.0 eq) propargylamine hydrochloride (2.16
g, 0.0235 mol, 1.0 eq) and K2CO3 (6.50 g, 0.0472 mol, 2.0 eq)
were taken in acetonitile (50 mL), then the reaction mixture
was heated at 60 °C for 3 h. The reaction was monitored by
using TLC, after completion of the reaction, acetonitile was
evaporated by high vacuum below 50 °C added EtOAc and
water. Organic layer was separated dried and concentrated.
The resultant crude was purified by column chromatography
by using EtOAc and n-hexane as a mobile phase resulted 3.1
1
g compound 7 as a brown thick mass. H NMR (400 MHz,
DMSO); δ 7.99 (d, 1H, Ar-H), 7.80 (dd, 1H, Ar-H), 7.78-7.68
(dd, 2H, Ar-H), 5.10 (d, 1H, NH-CH), 4.12 (d, 2H, NH-CH2),
3.77 (s, 1H, CH),3.09 (m, 1H, CO-CH), 2.86 (dd,1H, CO-
CH). Mass: m/z calcd185.07, found m/z 186.1 (M+1)+. HPLC
purity (%): 98.58.
Synthesis of (S)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-
inden-1-amine or S-isomer (6): A solution of N-(prop-2-yn-
1-yl)-2,3-dihydro-1H-inden-1-amine (10) (60 g, 0.531 mol,
1.0 eq), was taken in isopropyl alcohol (300 mL, 5 V) and
methanol (420 mL, 7 V), D(-) tartaric acid was added and
heated for 70 °C for 3h.The formed sold was filtered. The
tartarate salt was basified by using aqueous NaHCO3 solution
and extracted with EtOAc. Organic layer was dried and concen-
trated under vacuum yielded 28 g (42 %) compound 6 as a
brown thick mass. 1H NMR (400 MHz, DMSO) δ 7.62 (d, 1H,
Ar-H), 7.40-7.28 (m, 3H, Ar-H), 4.82-4.80 (m, 1H, NH-CH),
4.00 (s, 2H, NH-CH2), 3.78 (1H, acetyl CH), 3.15-3.07 (m,
1H, Ar-CH), 2.92-2.84 (m, 1H, Ar-CH), 2.48-2.16 (m, 2H,
CH-CH2). Mass: m/z calcd. 171.10, found m/z 172.0 (M+1).
HPLC Purity (%): 99.20. Chiral HPLC (%): 99.70.
Synthesis of N-allyl-2,3-dihydro-1H-inden-1-amine or
allyl impurity (4): A solution of N-(prop-2-yn-1-yl)-2,3-
dihydro-1H-inden-1-amine (10) (10 g, 0.0584 mol,1.0 eq),
Lindlar catalyst (1.0 g, 10 % w/w) and catalytic amount of
pyridine (0.456 g, 0.00584 mol, 0.1 eq) were taken in methanol
(100 mL) and were hydrogenated by using hydrogen balloon
pressure conditions for 6 h at ambient temperature. The
reaction was monitored by using TLC, after completion of the
reaction, the mixture was filtered through celite bed, MeOH
was evaporated by high vacuum below 50 °C. The resultant
crude was titrated by using EtOAc and n-hexane yielded 8.5 g
Synthesis of N-(2-chloroallyl)-2,3-dihydro-1H-inden-
1-amine or chloro allyl impurity (5&5a): A solution of N-
(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine (10) (10 g,
0.0584 mol, 1.0 eq), was taken in concentrated HCl (40 mL)
and were heated for 6 h at 60 °C. The reaction was monitored
by using TLC. After completion of the reaction, the reaction
mixture was cooled to room temperature basified with aqueous
NH3 solution and extracted with EtOAc dried and concentrated.
The resultant crude was purified by column chromatography
by using EtOAc and n-hexane as a mobile phase resulted 4.2 g
compound 5 and 2.8 g compound 5a.
1
(84.5 %) compound 4 as a brown colour oil. H NMR (400
MHz, DMSO); δ 7.32 (dd, 1H, Ar-H), 7.21-7.14 (m, 3H, Ar-
H), 5.93-5.86 (m, 1H, =CH), 5.23-5.03 (m, 2H, =CH2), 4.10
(t, 1H, NH-CH), 3.60 (bs, 1H, NH) 3.29-3.22 (m, 2H, NH-
CH2), 2.89-2.69 (m, 2H,Ar-CH2), 2.49-2.27 (m, 2H, CH-CH2).
Mass: m/z calcd. 173.12, found m/z 174.1 (M+1). HPLC purity
(%): 91.70.
1
Spectral data of compound 5: H NMR (400 MHz,
DMSO); δ 7.66 (d, 1H, Ar-H), 7.40-7.29 (m, 3H, Ar-H), 5.89-
5.70 (d, 2H, =CH2), 4.85 (m, 1H, NH-CH), 4.00 (m, 2H, NH-

Vol. 29, No. 6 (2017)
Synthesis and Characterization of Impurities in Rasagiline 1359
CH2), 3.17-2.85 (m, 2H,Ar-CH2), 2.49-2.15 (m, 2H, CH-CH2).
Mass: m/z calcd. 207.08, found m/z 208.1 (M+1). HPLC Purity
(%): 95.60.
N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine (10)
converted into allyl impurity (4) by using lindlar catalyst with
good yield [15,16]. Markovnikov’s and anti Markovnikov’s
addition of HCl on triple bond of compound 10 resulted com-
pound 5 and compound 5a. The recemic compound 10 was
resoluted with D(-)tartaric acid resulted 99.7 % chiral pure
S-isomer (6) (Scheme-II).
1
Spectral data of compound 5a: H NMR (400 MHz,
DMSO); δ 7.66 (d, 1H, Ar-H), 7.40-7.29 (m, 3H, Ar-H), 6.12
(d, 1H, =CH-Cl), 5.58 (d,1H.), 4.85 (m, 1H, NH-CH), 4.00
(m, 2H, NH-CH2), 3.17-2.85 (m, 2H, Ar-CH2), 2.49-2.15 (m,
2H, CH-CH2). Mass: m/z calcd. 207.08, found m/z 208.1 (M+1).
Conclusion
In Scheme-I, allyl impurity (4) preparation, we are not
achieved yield and purity (72 % by HPLC) and isolation
problem was observed, followed Scheme-II with good yield
and purity (90 % by HPLC). Similarly keto impurity, S-isomer
and chloro ally impurity were prepared good yields.
RESULTS AND DISCUSSION
Numbers of routes are reported in the literature for the
synthesis of rasagiline and its recemic compound [5-11]. Our
synthesis commenced with commercially available 1-indanone
(8) and N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine
(recemic compound) (10). 1-Indanone (8) was converted to
1-indanamine (3) [12]followed by coupling with allyl bromide
[13] resulted allyl impurity (4). On the other hand 1-indanone
(8) was brominated [14] followed by coupling with propargyl-
amine hydrochloride resulted keto impurity (7) with good yield
(Scheme-I).
ACKNOWLEDGEMENTS
The authors are thankful to the Management of Dr. Reddy’s
Laboratories Ltd, Hyderabad, India for providing facilities to
carry out this work.
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5
5a
Scheme-II