A Collective Review of The Synthetic Approaches Disclosed in Prior Patents To Synthesize The Renowned Drug, Lamotrigine

Mediterranean Journal of
Pharmacy & Pharmaceutical Sciences ISSN: 2789-1895 online

www.medjpps.com ISSN: 2958-3101 print
REVIEW article
A collective review of the synthetic approaches disclosed in prior patents

to synthesize the renowned drug, Lamotrigine
Sanjay Sukumar Saralaya 1 * , Shridhara Kanakamajalu 2 and Shashikumar Somashekar Hiriyalu 3
1
Department of Chemistry, Sri Dharmasthala Manjunatheshwara Institute of Technology (SDM IT), Ujire, Dakshina Kannada and
affiliated to Visvesvaraya Technological University, Belagavi, Karnataka, India
2
Technical Coordinator, ArkGen Pharma Private Limited, Peenya Industrial Area, Bangalore, Karnataka, India
3
Independent Researcher, Sreenagar, Mysuru, Karnataka, India
*
Author to whom correspondence should be addressed
Received: 02-02-2024, Revised: 20-02-2024, Accepted: 23-02-2024, Published: 31-03-2024
Copyright © 2024 Saralaya et al. This is an open-access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
HOW TO CITE THIS

Saralaya et al. (2024) A collective review of the synthetic approaches disclosed in prior patents to synthesize the renowned drug,
Lamotrigine. Mediterr J Pharm Pharm Sci. 4 (1): 52-74. [Article number: 145]. https://doi.org/10.5281/zenodo.10698581
Keywords: Lamotrigine, synthesis, cyanation, condensation, cyclization, recrystallization
Abstract: In this review work, we have extracted the essential details from prior patents about the synthesis
of popular drug Lamotrigine. This initiative will provide a platform for the global researchers to invent new
or innovate over the existing synthetic routes to isolate Lamotrigine with good yield and purity. The details of
patents were sourced from “Google patents” search tool and the process specific details were elaborated with
reaction schemes. In this context, twenty-four reactions schemes were tabulated for the better understanding
of the disclosed ventures. The entire chronological exfoliation of details on the synthesis of Lamotrigine
provides a clear evolutional vision of its synthetic flourish towards drug commercialization.
Introduction
Lamotrigine 1 is a popular drug molecule (Table 1) preferably used for the treatment of disorders related to
central nervous system (CNS), specifically epilepsy [1-3]. It is a class-II drug molecule of the
Biopharmaceutical Classification System (BCS), exhibits poor solubility in aqueous media (0.17 mg/mL) at
ambient temperature and does not vary significantly with pH. Thus, the sparingly soluble nature of 1 in water
would necessitate the administration of large volume of drug solution to achieve the intended therapeutic
efficacy [4].
Initially, a few 3,5-diamino-triazine derivatives were prepared and their anti-malarial activity against
Plasmodium berghei was tested. Most of the compounds were found to be toxic at curative doses and hence
they are not investigated further because their low therapeutic ratio [5]. Under the context, a few fluoro/fluoro-
alkyl/phenyl-alkyl-1,2,4-triazines were synthesized and tested their efficacy against malaria. Most of the
compounds were found to be useful in the treatment of malaria [6]. In another study, anti-malarial drugs like
quinacrine, chloroquine and hydroxychloroquine were tested as anti-convulsants. Among them, only
hydroxychloroquine had exhibited relatively good activity profile [7]. These repurposing investigations had
led to the emergence of some novel 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines to treat CNS disorders,
as anticonvulsants. Additionally, these triazine derivatives are non-depressants and hence are superior to
phenobarbitone [8].
Saralaya et al. (2024) Mediterr J Pharm Pharm Sci. 4 (1): 52-74. Volume 4: Issue 1: Page 52
Table 1: Essential details of Lamotrigine 1
Drug name Lamotrigine

Trade name Lamictal, Subvenite
Other names BW-430C; BW430C; 3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
IUPAC name 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine
Drug class Phenyltriazine
Drug purpose Anti-convulsant/Anti-epileptic drug, effectively used to treat some types of epilepsy and bipolar type-I
disorder
CAS number 84057-84-1
Drug-Bank number DB00555
Molecular formula C9H7Cl2N5
Molar mass 256.09 g/mol
Pharmacokinetic Bioavailability (98%), Protein binding (55%), Elimination half-life (29 h) and Metabolism (Liver-
data mediated by UGT1A4)
Melting point 177-181oC
Water solubility 0.17 mg/L
Chemical structure H2N N NH2
N
N
Cl
Cl
1
Exfoliation of synthetic approaches: Miller and others [8] had reported the synthesis of some novel 3,5-
diamino-6-(substituted phenyl)-1,2,4-triazines and their use to treat psychiatric and neurological disorders (as
anticonvulsants, to treat epilepsy). The work reports the synthesis of 1 (Scheme 1) starting from 2,3-
dichloroiodobenzene 2, which was converted to 2,3-dichlorobenzoic acid 3 in the presence of Mg turnings,
iodine and solid carbon dioxide. 2,3-Dichlorobenzoyl chloride 4 was obtained by treating 3 with thionyl
chloride. It was converted to 2,3-dichlorobenzoyl cyanide 5 by the use of cuprous cyanide and potassium
iodide in xylene. The condensation of aminoguanidine bicarbonate 6b with 5 was done by the use of nitric
acid and the cyclization was imposed by aqueous potassium hydroxide to form 1 (mp. 216-218℃) with
relatively low yield [8, 9]. In line to this, synthesis and biological activity studies of a few structurally related
compounds were reported earlier [5, 6].
Cl Cl O Cl O Cl O
Cl I Cl Cl Cl
Mg, I 2, dry CO2 OH SOCl2 Cl CuCN, KI
N
77.6% 85.0% 94.0%
2 3 4 5
Cl O NH2 Cl
Cl Cl
HN NH HNO 3, KOH, H 2O
N + NH2 15.6% N
N
5 .H2CO 3
6b H2N N NH2
1
Scheme 1: Synthesis of 1 starting from 2 as per Miller et al. [8].
Sawyer and others [10] had illustrated the synthesis and formulation methodology of novel 1 isethionate
(Scheme 2), a salt of parent drug 1. The salt formed is highly water soluble and hence facilitates parenteral
administration in the form of a sterile aqueous solution suitable for injection. The condensation of 5 with 6b
in the presence of nitric acid gave 1 (mp. 216-218oC), but the same reaction driven by concentrated sulphuric
acid gave 1 (mp. 216-218oC) with relatively high yield. It was converted to isethionate (mp. 242-243oC) either
by the use of sodium isethionate or isethionic acid [10].
Cl Cl N NH2 HNO 3 driven H2N N NH2
HN NH 15.6% N
N
O + NH2
5 .H2CO 3 Cl
41.6%
6b Cl
H2SO4 driven
1
Isethionic acid Sodium isethionate

40.0% 72.0%
1 isethionate
Scheme 2: Synthesis of 1 and its isethionate salt from 5 as per Sawyer et al. [10].
Winter et al. [11] had demonstrated a novel photo-chemical process to synthesize 1 and its pharmaceutically
acceptable acid addition salts (Scheme 3a-c). 2-(2,3-Dichlorophenyl)-2-oxoacetamide 7 was condensed with
6h in the presence of ethanolic hydrochloric acid to isolate (2E)-2-[(diaminomethylidene)hydrazinylidene]-2-
(2,3-dichlorophenyl)acetamide 8 (E). It was cyclized by the use of aqueous potassium hydroxide under varied
photochemical mediations to form 1 in moderate yields (mp. 218-222℃). In another example, (2E,Z)-1-(2,3-
dichlorophenyl)-2-(hydroxyimino)ethanone 11 (E,Z) was condensed with 6 under the influence of
hydrochloric acid to isolate N''-[(2E)-1-(2,3-dichlorophenyl)-2-(hydroxyimino)ethylidene]carbonohydrazonic
diamide 9 (E). It was treated with thionyl chloride in toluene to achieve the dehydration to generate N''-[(E)-
cyano(2,3-dichlorophenyl)methylidene]carbonohydrazonic diamide 10 (E). It was cyclized by the use of 1-
propanol under varied photochemical mediations to isolate 1 in good yields (mp. 218-220℃). Furthermore, 1
was treated with isethionic acid to form 1 isethionate (mp. 242-243℃) (Scheme 3a). The work had
demonstrated the condensation of 1-(2,3-dichlorophenyl)ethanone 12 with 3-methylbutyl nitrite 13 either by
HCl purge or butoxide pathway to isolate 11 (E,Z). Additionally, synthesis of 12 was achieved by the use of
distinct key starting materials like 2 or 1,2-dichlorobenzene 14 or 2,3-dichlorobenzaldehyde 15 in reasonably
good yields (Scheme 3b). The work had provided a few illustrations to condense 14 with ethyl amino (oxo)
acetate 17 under the mediation of n-BuLi to isolate 7 in moderate yields (Scheme 3c) [11].
NH2 .HCl
O H2N
Cl O NH EtOH, HCl, NaOH Sunlight
+ HN
83.0%
Cl NH2 Sunlight/Lamp H2N N NH2
6h
RT/Lamp N
7 H2N NH2 N
N Reflux/Photo reactor Cl
Cl N
Cl
Cl O KOH, H 2O Reflux/Lamp 1
NH2 56.0%
8 (E)
H2N H2N NH2

Cl Cl NH2
N
N N SOCl 2, Toluene Cl N
Cl
N 24.0%
N
OH
9 (E) 10 (E)
HCl 73.0% 1-propanol 150W lamp

60.0%
Cl Cl OH 8W lamp H2N N NH2
N
Hg lamp N
N
O 51.0%
11 (E,Z)
Hg lamp Cl
+ 73.0% Cl
H2N Hg lamp 1
NH 57.0%
HN
NH2
6
Isethionic acid
a) 70.0%
1 1 isethionate
b) 40.0%
Isethionic acid
Scheme 3a: Synthesis of 1 by the photochemical pathway as per Winter et al. [11].
HCl route
Cl O H Cl O
H H
Cl H 46.0% Cl
H
H
H + H
N
H OH
O N butoxi de route
12 13 11 (E,Z)
O 73.8%
Cl
Cl BuLi , Aceti c anhydride
12
75.0%
14
O Cl OH Cl
Cl Iodomethane, Mg turni gs Cl Sodi um hypochl orite
H
12
90.0% 65.0%
15 16
Cl
I Cl Mg turnigs, acetyl chl oride, Ferric chloride
12
60.66%
2
Scheme 3b: Synthesis of 11 from 14, 15 & 16
Cl Cl O Cl Cl
O n-BuLi O
O
+ NH2 32-52.0% O
14 17 H2N
7
Scheme 3c: Synthesis of 7 from 14 and 17.
Lee [12] had reported the synthesis of 1 and its pharmaceutically acceptable acid addition salt 1 isethionate
from 12 (Scheme 4). In fact, 12 was prepared via past disclosed process from 2 or 14 or 15 [10]. An oxidation
driven by potassium permanganate (KMNO4) in alkaline medium had converted 12 to its acid derivative (2,3-
dichlorophenyl)-(oxo)-acetic acid 18. It was treated with hydrazinecarbothioamide 19 in the presence of
aqueous sodium hydroxide to obtain 6-(2,3-dichlorophenyl)-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one 20.
The reaction of methyl iodide (CH3I) with 20 in alkaline medium gave 6-(2,3-dichlorophenyl)-3-
(methylsulfanyl)-1,2,4-triazin-5(4H)-one 21. It was treated with phosphorous oxychloride (POCl3) to isolate
5-chloro-6-(2,3-dichlorophenyl)-3-(methylsulfanyl)-5,6-dihydro-1,2,4-triazine 22. An autoclave mediated
impact of saturated ammonia (NH3) gas in ethanol at 180oC for about 72 h had converted 22 to 1 (mp. 218oC).
It was treated with isethionic acid via two different methods to isolate 1 isethionate (mp. 242-243oC).
Cl Cl Cl Cl OH Cl O Cl
n-BuLi Iodomethane
Acetic anhydride O Sodium hypochlorite Cl Mg turnings Cl
H
75.0% H 65.0% 90.0%
14 12 H
H 16 15
Mg turnings
60.66% Acetyl chloride
Ferric chloride
Cl
I Cl
2
NH2
Cl Cl S Cl Cl O H
KMNO 4 , KOH, Pyridine O 19 NHNH2 N
12 S
67.8% NaOH, H 2 O
OH N N
18 O 48.0% 20 H
63.0% NaOH, Methyl iodide
Cl Cl Cl Cl Cl O H
NH 3 , Autocl ave N POCl 3
N
1 S H S H
o
180 C N N H 80.0% N N H
22 H 21 H
Isethionic acid
40.0%
1 isethionate
72.0%
Scheme 4: Synthesis of 1 and its isethionate salt from 12 as per Lee [12].
Vyas [13] had demonstrated the conversion of 4 to 5 by the use of copper cyanide (CuCN) in acetonitrile and
toluene. The condensation of 5 with 6b was executed in the presence of sulphuric acid and aqueous acetonitrile
to isolate (2-E,Z)-2-[cyano(2,3-dichlorophenyl)methylidene]hydrazinecarboximidamide 23. It was cyclized
under reflux by the impact of potassium hydroxide solution to get 1 (mp. 216-218oC) (Scheme 5).
NH2
NH2
HN NH H
NH2 HN N
N
N
Cl Cl Cl O .H 2 CO 3
Cl Toluene Cl 6b Cl
O
CuCN, ACN H 2 SO 4 , H2 O, ACN, NaOH
N
Cl
4 5 23
KOH, H2 O, ref lux
1
43.75% of overall yield
Scheme 5: Synthesis of 1 from 4 as per Vyas [13].
Edmeades and others [14] had reported a moderate yield process for the synthesis of 1. Additionally, synthesis
and characterization of two impurities of 1 were reported to facilitate the analysis of 1. These impurities would
act as reference standards to estimate the potential impurities in the drug (Scheme 6). Hydrogen peroxide
(H2O2) mediated oxidation of 12 in the presence of sodium hydroxide and tert-butyl alcohol gave 3. It was
treated with thionyl chloride in the presence of pyridine in toluene to form an un-isolated 4. An insitu addition
of cuprous cyanide (CuCN) and potassium iodide to 4 had resulted in the formation of 5. The condensation of
5 with 6b was achieved by the use of sulphuric acid to isolate N''-[(E,Z)-cyano(2,3-dichlorophenyl)
methylidene]carbonohydrazonic diamide 24. It was effectively cyclized in the presence of n-propanol under
reflux to get crude 1, its recrystallization from n-propanol gave 1. The novel potential degradation by-product
3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-5(4H)-one A was prepared by treating 1 with sodium hydroxide
solution. Another novel potential contaminant N-[5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]-2,3-
dichlorobenzamide B was formed by the un-wanted side reactions during the drug synthesis. It was prepared
by treating 1 with 4 in the presence of pyridine.
Cl H Cl O Cl O
Cl H2O2, NaOH Cl Toluene, py ridine
Cl
O OH Cl 5
SOCl2, KI, CuCN
75.0% 77.0%
12 6b
3 4
H2SO4, NaOH 66.0%
H
H2N N O H2N NH2
N 74.7%
N H2N N NH2 N
N
Cl N
N
Cl 1-propanol
N
A Cl Cl
Cl 90.0%
Cl Cl
Cl 4 1 24
O
36.0%
HN N NH2
N
N
Cl
Cl
B
Scheme 6: Synthesis of 1 from 12 as per Edmeades et al. [14].
Nadaka and others [15] had illustrated a simple process for the synthesis of 1 from 5 (Scheme 7). The
condensation of 5 with 6b was achieved in the presence of polyphosphoric acid in acetonitrile to get 23.
Similarly, the reaction of 5 with aminoguanidine 6 under similar conditions with the use of polyphosphoric
acid and monoglyme gave 23. The cyclization of 23 was done by the use of n-propanol under reflux to isolate
crude 1, it was recrystallized from n-propanol or n-propanol and dimethyl sulphoxide mixture to obtain pure
1 (mp. 216-218oC).
NH2
HN NH Polyphosphoric acid, ACN, NaOH NH

NH2 H
Cl O 84.0% H2N N
.H 2 CO 3 N
Cl N
6b 1-propanol
N + Cl 89.53%
1
NH2
5
HN NH Polyphosphoric acid, monoglyme Cl
NH2 67.0% 23
6
Scheme 7: Synthesis of 1 from 5 as per Nadaka et al. [15].
Guntoori and others [16] had reported an efficient novel process for the synthesis of 1 and its monohydrate
form (Scheme 8). In an illustration, the condensation of 5 with 6h was done in the presence of methanesulfonic
acid (MSA) and dimethylformamide. To the mixture added thionyl chloride as a dehydrating agent followed
by the addition of aqueous potassium hydroxide had resulted in the formation of 24. A strong reflux of 24 in
isopropyl alcohol and potassium hydroxide gave 1 monohydrate. In another example, a direct process was
revealed by the condensation of 5 with 6h in the presence of MSA and dimethylformamide. A sequential
addition of thionyl chloride and potassium hydroxide had resulted in the formation of 1 monohydrate. The
recrystallization of isolated monohydrate form of 1 in isopropyl alcohol gave 1 (in its anhydrous form) (216-
217oC).
Methanesul fonic aci d IPA, KOH

24 1 Monohydrate
DMF
Cl O 82.0% of overall yield
T hionyl chl oride
Cl 6h IPA
1
N 94.0%
5 Methanesul fonic aci d
DMF
1 Monohydrate
T hionyl chl oride
78.0%
KOH
Scheme 8: Synthesis of 1 and its monohydrate form from 5 as per Guntoori et al. [16].
Radhakrishnan and others [17] had illustrated an improved process for the synthesis of 1 with better yield and
commercialization feasibility (Scheme 9). 2,3-Dichloronitrobenzene 25 in methanol was reduced in the
presence of Raney nickel in an autoclave to get 2,3-dichloroaniline 26. It was treated with sodium nitrite in
acidic medium followed by the addition of sodium cyanide (NaCN) solution to isolate 2,3-dichlorobenzonitile
27. It was refluxed in the presence of sodium hydroxide solution in methanol to get the hydrolyzed derivative
3. It was treated with thionyl chloride to form 4 and then the addition of copper cyanide and potassium iodide
in chlorobenzene had resulted in the formation of 5. The condensation of 5 with 6b was achieved by the use
of sulphuric acid and para-toluene sulfonic acid (PTSA) in toluene followed by the addition of sodium
methoxide (NaOMe) to get crude 1. It was recrystallized from methanol to isolate pure 1.
Cl O Cl Cl Cl O
Cl N Cl NH2 Cl Cl
O N OH
MeOH, Raney -Ni H 2 SO 4 , NaNO2 NaOH, MeOH
25 97.18% 26
NaCN, H2 O
27 74.8% 3
94.2%
Thiony l chloride 91.2%
6b Cl O Cl O
H 2 SO 4 , PTSA, toluene
Cl Cl
Sodium methoxide CuCN, KI, Chlorobenzene Cl
1 N
56.25% 98.44%
Crude
5 4
MeOH 88.88%
1
Scheme 9: Synthesis of 1 from 24 as per Radhakrishnan et al. [17].
Manjunatha and others [18] had illustrated an improved process for the synthesis of 1 and its monohydrate
form (Scheme 10). The addition of thionyl chloride to 3 gave 4. It was treated with copper cyanide (CuCN)
in toluene at 160-165oC to obtain the oily residue, and after hexane recrystallization 5 was isolated. The
condensation of 5 with 6b was performed by the use of various aqueous acids (sulphuric acid, hydrobromic
acid, hydrochloric acid, nitric acid and phosphoric acid) in the presence or absence of organic solvent to get
Schiff base 24 with varied yields. The mixture of 24 and aqueous isopropyl alcohol was refluxed to isolate 1
monohydrate. It was dissolved in aqueous isopropyl alcohol, clarity filtered, cooled, filtered and dried at 100oC
to isolate 1.
6b
Cl Cl Cl Aq. acid Cl
SOCl2 CuCN, toulene NaOH
Cl Cl Cl Cl
95.76% 73.30% 39.6-78.0%
O OH O Cl O N
N N
3 4 5
N
NH2
H2N
24
74.76% IPA/H 2 O
Cl
Cl
IPA/H2O
1 H2N
84.50% N
N N
NH2 H2O
1 Monohydrate
Scheme 10: Synthesis of 1 from 3 as per Manjunatha et al. [18].
Numerous synthetic methods of 1 were disclosed in the prior arts with some disadvantages such as, formation
of an aggressive reaction medium, long reaction time, multi-step pathway, low yield, release of large quantity
of effluents, harmful radiation utility, use of expensive reagents, involvement of hazardous chemicals,
complicated synthesis, un-economical synthetic pathway etc. To overcome these drawbacks, many researchers
had started to design some novel and simple synthetic routes to isolate 1. In this context, Jozsef and others
[19] had reported a new process for the synthesis of 1 in high purity with minimum process steps (Scheme
11). MSA in methanol was used to convert 6b to its dimesylate salt 6d. The condensation of 5 with 6d was
executed under the presence of MSA in acetonitrile to form the un-isolated 23. It was cyclized in-situ by the
addition of magnesium oxide (MgO) in water to get crude 1 (mp. 212-216oC). Upon recrystallization from
acetone gave pure 1 (mp. 215-219oC).
Cl O
MSA/ACN
Cl MgO, H 2O Acetone
N
+ NH2
1 (93.10%, crude yield)
70.0%
1
5
HN NH
NH2
O
S OH
O 2
6d
OH
Methanol
S O
88.10%
O
NH2
HN NH
NH2
H2CO 3
6b
Scheme 11: Synthesis of 1 from 5 using MSA as per Jozsef et al. [19].
Pere et al. [20] had demonstrated a viable process to isolate 1 in good yield with shortened reaction time
(Scheme 12). The condensation of 5 with 6b was achieved in the presence of alone MSA or MSA and toluene
to isolate 24. It was cyclized in the under the impact of some solvents like, ethanol or ethanol (96%) or
isopropyl alcohol or aqueous isopropyl alcohol etc. to isolate pure 1 (mp. 217℃) without the additional
recrystallization steps [20].
M ethanesul foni c aci d N

NaOH
Cl O Cl
Cl 6b 82.0% Cl N NH2
N
N M ethanesul foni c aci d NH2
T ol uene, NaOH
5 24
79.0%
EtOH
83.0%
IPA
90.0%
1
IPA/H 2 O
82.0%
EtOH (96%)
90.0%
Scheme 12: Synthesis of 1 from 5 as per Pere et al. [20]

Geza and others [21] had demonstrated an impurity free and industrially viable process for the synthesis of 1
(Scheme 13). {[(E,Z)-(2,3-Dichlorophenyl)methylidene](phenyl)ammonio}oxidanyl 28 was treated with
potassium dihydrogenphosphate and sodium cyanide in aqueous methanol to get (2E,Z)-(2,3-
dichlorophenyl)(phenylimino)acetonitrile 29. It was treated with thionyl chloride in aqueous ethanol (ethanol
hydrochloric acid solution) and exposed to ethanol saturated with ammoniac to obtain the hydrochloride salt
of (2E,Z)-2-(2,3-dichlorophenyl)-2-(phenylimino)ethanimidamide 30. It was coupled with 6b in the presence
of aqueous hydrocghloric acid to isolate the dihydrochloride salt of (2E,Z)-2-[2-amino-1-(2,3-
dichlorophenyl)-2-iminoethylidene]hydrazinecarboximidamide 31h or its free base 31. The cyclization of 31h
or 31 in the presence of N,N-dimethylformamide gave 1 hydrochloride (mp. 233-235oC) or 1 (mp. 215.5-
216.5oC).
KH 2 PO 4 , methanol SOCl 2 , ethanol

O + NaCN, H 2 O NH3
N N N
H2N
H
N .HCl
NH
Cl Cl Cl
Cl Cl Cl
28 29 30
Aq. HCl 6b
91.5%
H2N NH
.2HCl NH
DMF, IPA
N
1 H2N
HCl 60.5%
NH Aq. NaOH
Cl
Cl
31h
Aq. NaOH
H2N NH
NH
DMF, IPA
N
1 H2N
66.7%
NH
Cl
Cl
31
Scheme 13: Synthesis of 1 from 28 as per Geza et al. [21].
Arul and others [22] had reported an industrially feasible high yield process for the synthesis of 1 having a
better flowability and satisfactory impurity profile (Scheme 14). The condensation of 5 with 6b was achieved
in the presence of phosphorous penta oxide (P2O5) and MSA to isolate the novel monomesylate salt 23m. The
cyclization of 23m was induced by the use of methanol and potassium carbonate (K2CO3) to obtain crude 1.
It was recrystallized from isopropyl alcohol to isolate 1 (mp. 216-217oC).
Cl O NH2 NH2
Cl H
HN NH P2O 5/MSA HN N CH 3OH/K 2CO 3
N + NH2
103.52%
.CH3SO3H
N
N
89.5%
1
.H 2 CO 3
Crude
5 Cl
6b
72.0% IPA/H 2O
Cl
23m
1
Crude
Scheme 14: Synthesis of 1 from 5 as per Arul et al. [22].
Dirk and others [23] had demonstrated a high yield route for the synthesis of 1 from 2,3-dichloro toluene 32
(Scheme 15). The conversion of 32 to 2,3-dichlorobenzotrichloride 33 was achieved in the presence of
chlorine gas (Cl2) in carbon tetrachloride (CCl4). The reduction of 33 to 4 was done by the use of zinc chloride
(ZnCl2). It was treated with cuprous cyanide in toluene to isolate 5. Meanwhile, cuprous cyanide was
recovered from the inorganics isolated (CuCl). The condensation of 5 with 6b was performed in the presence
of sulphuric acid and later treated with sodium hydroxide to isolate 24. It was treated with aqueous n-propanol
to isolate the crude 1 and the pure 1 was obtained upon recrystallization from aqueous n-propanol. Similarly,
the cyclization in the presence of n-propanol was also reported to isolate pure 1.
H Cl
H Cl 2, CCl4, HVD Cl ZnCl2, H2O CuCN, tol uene
4 5
H a) 81.6% Cl a) 91.0% 94.2%
Cl Cl Cl Cl CuCN (R): 94.2%
b) 97.1% b) 88.0%
32 33
c) 95.2% 6b a) 76.8%
H 2 SO4 , NaOHb) 85.6%
Cl
H2N N Cl
N
H2N N
24
a) n -propanol , water a) Crude: 88.2%
b) n -propanol a) Pure: 89.0%
b) 84.7%
Scheme 15: Synthesis of 1 from 32 as per Dirk et al. [23].
Patel and others [24] had reported the synthesis of intermediates of 1 in high yield (Scheme 16). Nitric acid
impact on 32 at 140oC in an autoclave gave 3. It was treated with thionyl chloride to obtain 4. Cyano-
dehalogenation of 4 in the presence of cuprous cyanide and phase transfer catalyst in xylene or mono-chloro
benzene (MCB) gave 5. The coupling of 5 with 6b was achieved by the use of aqueous sulphuric acid, followed
by the addition of sodium hydroxide solution gave 23. It was refluxed with aqueous potassium hydroxide
solution to isolate 1.
H
H HNO3, Autoclave SOCl2 CuCN, xylene, TBAI
3 4
H 90.63% 91.19% 81.15%
Cl Cl
32 6b
CuCN, MCB, TBAI
Aq. H2SO4
79.06% NaOH
5 23
CuCN, xylene, TBAB
70.30%
79.84%
Aq. KOH
CuCN, MCB, TBAB
80.63%
1
Scheme 16: Synthesis of 1 from 32 as per Patel et al. [24].
Paul and others [25] had demonstrated an improved process for the synthesis of 1 (Scheme 17). The disclosure
reports the conversion of 4 to 5 in the presence of copper (I) iodide and sodium cyanide (NaCN). The
condensation of 5 and 6b was achieved in the presence of MSA and sulphur trioxide to isolate the intermediate
sulphate salt 24s. It was subjected for cyclization by the use of sodium hydroxide solution to isolate 1
monohydrate, which upon recrystallization from aqueous isopropyl alcohol gave 1. A similar approach was
adopted to get 1 by avoiding the isolation of the intermediate salt 24s. In another example, the condensation
of 5 with 6b was undertaken in the presence of tetrafluoroboric acid to obtain the intermediate
tetrafluoroborate salt 24t. It was cyclized in the presence of sodium hydroxide solution to obtain 1. A similar
pathway was adopted to isolate 1 by not isolating the intermediate salt 24t. In another example, condensation
of 5 with 6b was achieved by the use of tetrafluoroboric acid and water. An azeotropic distillation of water
was done to push the reaction for completion and finally alkali mediation gave 1. The novel salts reported are
highly soluble in most organic solvents, thus contributing to reaction rapidity.
Cl O Copper(I)iodide
Cl O 6b MSA
Cl Cl SO 3 NaOH
NaCN
Cl 24s Crude 1 Monohydrate
N H 2O
80.0% 75.0%
4 5
IPA, H2O
6b MSA
SO 3 IPA, H2O
1 Crude 1
NaOH, H2O
Cl O 6b
Cl Tetrafluoroboric acid
24t Crude 1 Monohydrate
N NaOH, H2O
5
IPA/H2O
6b
Tetrafluoroboric acid IPA/H2O
1 Crude 1
NaOH, H2O
6b
Tetrafluoroboric acid
H 2O
1 Monohydrate
NaOH, H2O
45%
Scheme 17: Synthesis of 1 from 4 as per Paul et al. [25].
Jiang [26] had disclosed a novel one step method to synthesize 1 from 5 (Scheme 18). The condensation of
6b with 5 was executed under acidic condition (sulphuric acid or phosphoric acid) to form an intermediate
Schiff base 23. It was directly heated in the presence an alkaline medium (sodium/potassium/lithium
hydroxide or soium/potassium tertiary butoxide or sodium/potassium/lithium carbonate or tripotassium
/trisoium phosphate) and silica gel or alumina through microwaves to induce the cyclization to get 1 (mp. 216-
217oC).
H 2SO 4, water, MSA

Silica gel, NaOH, MW
78.0%
H 2SO 4, water, MSA
58.0%
H 2SO 4, water, MSA
Alumina, NaOH, MW
70.0%
H 2SO 4, water, MSA
72.0%
Phosphoric acid, water, MSA

42.0%
H 2SO 4, water, MSA
Silica gel, KOH, MW
71.0%
H 2SO 4, water, MSA
35.0%
Cl O NH2
H 2SO 4, water, MSA
Cl Silica gel, K 2CO 3 , MW
1
HN NH
N + NH2
55.0%
H 2SO 4, water, MSA
.H 2 CO 3 Silica gel, Na 2CO 3 , MW
5
54.0%
6b
H 2SO 4, water, MSA
Silica gel, NaOtBu, MW
65.0%
H 2SO 4, water, MSA
Silica gel, KOtBu, MW
64.0%
H 2SO 4, water, MSA
Silica gel, Li 2CO 3, MW
56.0%
H 2SO 4, water, MSA
Silica gel, LiOH, MW
68.0%
H 2 SO 4 , water, MSA
Silica gel, K 3PO 4, MW
62.0%
H 2SO 4, water, MSA

Silica gel, Na 3PO 4, MW
60.0%
Scheme 18: Synthesis of 1 from 5 under acidic medium and microwaves impact as per Jiang [26].
To overcome the process related issues, Yang et al. [27] had demonstrated a simple one step n-propanol driven
cyclization process to synthesize 1 from 23 (Scheme 19). This disclosure avoids the use of toxics and harmful
chemicals with an improved yield (theoritical) of 1 [27].
NH2
H
HN N n-propanol IPA /H 2O
N 1 1
N
Crude
Cl
Cl
23m
Scheme 19: Synthesis of 1 from 23 as per Yang et al. [27].
Carmen [28] had demonstrated the synthesis of 1 in high yield with least impurities starting from 23 (Scheme
20). The cyclization of 23 was achieved by the use of isopropanol to get crude 1. It was treated with aqueous
MSA to obtain methanesulfonate salt f 1. It was neutralized by the addition of aqueous sodium hydroxide to
isolate 1 monohydrate. It was refluxed in methanol to get 1 (mp. 216oC). A similar salt formation of 1
(anhydrous) using MSA and desalting by sodium hydroxide was also illustrated to obtain 1 monohydrate.
NH2
H
HN N Isopropanol Aq. MSA
N 1 1
N
Crude Methane sulfonate
Cl
Aq. NaOH, Methanol
Cl
23
1
Monohydrate
Methanol
1
Overall yield: 76.8%
Scheme 20: Synthesis of 1 from 23 as per Carmen [28].
Yiyue and others [29] had illustrated the synthesis of 1 (Scheme 21) by the controlled cyclization of Schiff
base by avoiding the formation of ketone derivative (impurity). The condensation of 5 with 6b was done by
the use of sulphuric acid and water, followed by the addition of base (sodium hydroxide or potassium
hydroxide or sodium carbonate) to isolate the Schiff base 23. It was refluxed in alcohol (methanol or ethanol
or isopropyl alcohol) to isolate crude 1. Furthermore, the process of activated carbon decolorizing,
recrystallization, cleaning and vacuum-drying gave 1.
Cl O NH2 NH2
H 2SO 4, w ater
Cl H
HN NH NaOH, H 2O HN N CH 3OH, reflux
N + NH2 99.3% N
N
99.6%
1
Crude
.H 2 CO 3
5 Cl
6b
IPA, H 2O
Cl
23
1
Cl O NH2 NH2
H 2SO 4, w ater
Cl H
HN NH KOH, H 2O HN N C 2H 5OH, reflux
N + NH2 99.1% N
N
98.3%
1
Crude
.H 2 CO 3
5 Cl
6b
IPA, H 2O
Cl
23
1
Cl O NH2 NH2
H 2SO 4, w ater
Cl H
HN NH Na 2CO 3, H2O HN N IPA, ref lux
N + NH2 98.9% N
N
99.3%
1
Crude
.H 2 CO 3
5 Cl
6b
IPA, H 2O
Cl
23
1
Scheme 21: Synthesis of 1 from 5 as per Yiyue et al. [29].
Luo and Li [30] had reported an improved and optimized process for the synthesis of 1 (Scheme 22). The
disclosed process involves cyanation of 4 to get 5 using potassium hexacyanoferrate in the presence of phase
transfer catalyst and potassium iodide in toluene. The condensation of 5 with 6b was done using aqueous
sulphuric acid. The cyclization of 24 was achieved by the influence of aqueous hydroxide to get 1. A few
experiments were executed to achieve catalyst screening and catalyst level ratio optimization in the cyanation
step using phase-transfer catalysts like (alone/mixture) benzyltriethylammoinium chloride, tetra-
butylammonium chloride, tetra-butyl ammonium bromide or 4-butyl ammonium hydrogen sulphate.
Similarly, metal iodide used for the cyanation was potassium iodide or silver iodide.
Cl Cl 6b Cl
T BAB, KI, K4Fe(CN)6 Aq. H2SO4
T oluene NaOH
Cl Cl Cl
70.4-96.7% 82.0%
O Cl O N
N N
4 5 N NH2
NH2
24
93.5% KOH, H 2 O
1
Crude
90.66% IPA/H2O
Scheme 22: Synthesis of 1 from 4 as per Luo and Li [30].
Cheng and others [31] had illustrated an improved synthesis technique of 1 (Scheme 23) with enhanced atom
economy and better purity. The treatment of 3 with thionyl chloride followed by the addition of cuprous
cyanide gave 5 (as crude liquid). The condensation of 5 with 6b was performed in the presence of sulphuric
acid and an azeotropic solvent (methanol or toluene). An in-situ cyclization by the addition of aqueous alkali
gave 1. A similar attempt in the absence of methanol or toluene for the condensation stage, gave poor yield of
1. This work emphasizes the importance of water removal in the condensation stage using suitable solvents.
The removal of water had increased the rate of reaction and the overall process yield to 93-97% from 40-42%
[31].
Cl Cl 6b
SOCl2 CH3OH, H2SO4
1
Cl CuCN Cl NaOH, H2O
Overall yield: 95.2-97.0%
O OH O
N
3 5
Cl Cl 6b
SOCl2 H2SO4
1
O OH O
N
3 5
Cl Cl 6b
SOCl2 Toluene, H2SO4
1
O OH O
N
3 5
Scheme 23: Synthesis of 1 from 3 as per Cheng et al. [31].
Zou and others [32] had disclosed an improved method for preparing 1, which is distinct from the prior art
practices. The process involves the synthesis of four major imine type ligands in different experiments by the
use of benzoyl chloride 34, 4-methylbenzoyl chloride 40, 4-methoxybenzoyl chloride 44 to isolate ligand-1
39, ligand-2 41, ligand-3 43 and ligand-4 45 (Scheme 24a). Furthermore, 3-amino-1,2,4-triazine 46 was
halogenated in the presence of N-bromo succinamide (NBS) in N,N-dimethylformamide to get 3-amino-6-
bromo-1,2,4-triazine 47. It was subjected to amination in the presence of KMNO4 and liquid ammonia to
obtain 3,5-diamino 6-bromo-1,2,4-triazine 48. The coupling of 48 with 2,3-dichlorobenzene boric acid 49
was done by suzuki coupling pathway in N,N-dimethylformamide under the catalysis of
palladium/ligand/alkali to isolate 1 through column chromatography (Scheme 24b). The disclosed method
avoids the use of metal cyanide, and exhibited better reaction selectivity with high yield.
O NH2
TEA, CH2 Cl 2 SOCl 2
Cl + 66.43% 80.8%
HN N
O Cl
34 35
36 37
TEA, toluene N NH2

61.9%
38
N
NH
N
39
O a) TEA, CH2Cl 2 N
b) SOCl2
NH
Cl + 31 c) Toluene, TEA N
38
40 41
58.36%
N
a) TEA, CH2Cl 2 c) Toluene, TEA O NH
34 + 35 b) SOCl2
N
N
N NH2 O
O 43
N 54.56%
O 42
O
O a) TEA, CH2Cl 2
b) SOCl2
Cl + 31
c) Toluene, TEA
N
O 38 NH
44 N
45
62.42%
Scheme 24a: Synthesis of some ligands as per Zou et al. [32].
OH
Cl B
OH
Cl
49
N NH2 N NH2
N KMNO4 , liq. NH3 N K 3PO4, PdCl2, ligand 39, DMF, aq. EA
N N 1
Br 84.6% Br 85.6%
47 NH2
48
DMF, NBS, NaOH 81.7% 49
K 3PO4, PdCl2, ligand 41, DMF, aq. EA
N NH2 1
84.2%
N
N
46
49
1
83.8%
49
1
87.4%
Scheme 24b: Synthesis of 1 via Suzuki coupling as per Zou et al. [32].
Li [33] had reported an invention pertaining to a crystal form of 1 hydrate (form-A). The form-A prepared had
very high purity, good solubility and better chemical stability. These features will provide an essential
advantage for the drug formulation.
In summary: Numerous global researchers associated to various organizations have worked on the sample
preparation, process development, formulation and therapeutic studies of 1 (Table 2). Under the context, 24
reaction schemes were furnished for the clear understanding of prior art disclosures. A similar kind of
comprehensive review effort was made by us on a few popular drugs like Atovaquone [34], Parvaquone [35],
Buparvaquone [36], Zoledronic acid [37, 38] and Rasagiline [39]. Kumar R, et al., had reported a review
article which outlines the pharmacological importance and general synthetic strategies of various triazines
including 1. This review contribution had covered the brief details on 1,2,3-triazines (5 drug molecules), 1,2,4-
triazines (11 drug molecules) and 1,3,5-triazines (31 drug molecules) [40]. Our present review contribution is
very specific to 1 and contextually particular to the synthesis pathway. For an industrial suitability, multi-step
process pathways (more than 3 steps) are difficult to control with regard to achieve consistent yield and purity
of the intermediates and 1. Synthesis of 1 from 5 in minimum steps was found ideal for the commercialization
and hence the same was adopted in most of the disclosed reaction schemes.
Table 2: Patent assignee data (by an organization or an individual)
Ref. No. Application filed by (assignee)

[6] American home products corporation
[8] Wellcome foundation limited
[9] Burroughs wellcome corpotation
[12] Glaxo wellcome incorporated
[13] Sharad kumar vyas (Individual)
[14] Glaxo wellcome incorporated
[15] Chemagis limited
[16] Brantford chemicals incorporated
[17] RPG life sciences limited
[18] Jubilant organosys limited
[19] Richter gedeon vegyészeti gyár Rt. (Individual)
[20] Vita cientifica, S. L.
[21] Karl o helm AG, CF Pharma Gyogyszergyarto Kft
[22] Unichem laboratories limited
[23] Calaire chimie sas
[24] Ratnamani bio-chemicals and pharmaceuticals private limited.
[25] Lonza Ag (Individual)
[26] Jiang yong (Individual)
[27] Sanjin group hunan sanjin pharmaceutical company limited
[28] Medichem, S.A.
[29] Yancheng kaili pharmaceutical company limited
[30] Chengdu yilukang medical technology and service company limited
[31] Zhejiang qicai eco technology company limited
[32] Sanjin group hunan sanjin pharmaceutical company limited
[33] Shanghai okoda biomedical technology company limited
Conclusion: This review work indicates the sequential flourish of synthetic pathway of 1 adopted in prior
patents. Moreover, every reported work highlights the prior process drawbacks and emphasizes to provide an
improved process to facilitate large scale manufacturing of 1. In this work, we have considered all the
disclosed patents on the synthesis of 1 and specifically excluded the patents belonging to the same family.
Under the context, we could able to tabulate 24 reaction schemes as per the disclosures in prior arts regarding
the synthesis of 1. Among them, 18 disclosures had the presence of 5 as the starting material or as an
intermediate to obtain 1. Thus, the role of 5 in the synthesis of 1 is very significant towards the yield, purity
and commercial viability of the drug. This comprehensive review coverage can help the global researchers to
design their novel/innovative scalable synthetic strategy to isolate 1 under the green chemistry ideology in
near future.
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Acknowledgements: The authors would like to thank the governing officials of SDM Educational Society (Ujire-India) and
Alkem Laboratories Limited (Mumbai-India), for giving the support to complete this review initiative.
Author contribution: SSS & SK conceived and designed the study, collected data. SSS & SSH performed experiments and
collected and analysed data. SK performed analysis and interpreted data. All the authors approved the final version of the
manuscript and agreed to be accountable for its contents.
Conflict of interest: The authors declare the absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Ethical issues: Including plagiarism, informed consent, data fabrication or falsification, and double publication or submission
have completely been observed by authors.
Data availability statement: The raw data that support the findings of this article are available from the corresponding author
upon reasonable request.

A Collective Review of The Synthetic Approaches Disclosed in Prior Patents To Synthesize The Renowned Drug, Lamotrigine

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A Collective Review of The Synthetic Approaches Disclosed in Prior Patents To Synthesize The Renowned Drug, Lamotrigine

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Mediterranean Journal of

Pharmacy & Pharmaceutical Sciences ISSN: 2789-1895 online

A collective review of the synthetic approaches disclosed in prior patents

Received: 02-02-2024, Revised: 20-02-2024, Accepted: 23-02-2024, Published: 31-03-2024

HOW TO CITE THIS

Keywords: Lamotrigine, synthesis, cyanation, condensation, cyclization, recrystallization

Table 1: Essential details of Lamotrigine 1

Drug name Lamotrigine

Cl Cl N NH2 HNO 3 driven H2N N NH2

Isethionic acid Sodium isethionate

H2N H2N NH2

HCl 73.0% 1-propanol 150W lamp

63.0% NaOH, Methyl iodide

KOH, H2 O, ref lux

Scheme 5: Synthesis of 1 from 4 as per Vyas [13].

Scheme 6: Synthesis of 1 from 12 as per Edmeades et al. [14].

HN NH Polyphosphoric acid, ACN, NaOH NH

Methanesul fonic aci d IPA, KOH

Scheme 10: Synthesis of 1 from 3 as per Manjunatha et al. [18].

M ethanesul foni c aci d N

Scheme 12: Synthesis of 1 from 5 as per Pere et al. [20]

KH 2 PO 4 , methanol SOCl 2 , ethanol

Scheme 13: Synthesis of 1 from 28 as per Geza et al. [21].

Scheme 15: Synthesis of 1 from 32 as per Dirk et al. [23].

H 2SO 4, water, MSA

Phosphoric acid, water, MSA

H 2SO 4, water, MSA

Scheme 19: Synthesis of 1 from 23 as per Yang et al. [27].

Scheme 20: Synthesis of 1 from 23 as per Carmen [28].

Scheme 22: Synthesis of 1 from 4 as per Luo and Li [30].

TEA, toluene N NH2

Scheme 24a: Synthesis of some ligands as per Zou et al. [32].

Table 2: Patent assignee data (by an organization or an individual)

Ref. No. Application filed by (assignee)

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