CWPTEliS Imidazo pyridine derivatives containing morphoRne nucleus
5.1. Introduction
Heterocyclic compounds hold a special place among pharmaceutically significant
natural products and synthetic compounds [1, 2]. Nitrogen heterocycles are abundant in
nature and are of great significance to life because their structural subunits exist in many
natural products such as vitamins, hormones, antibiotics, and alkaloids as well as
pharmaceuticals, herbicides and many more compounds. The remarkable ability of
heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely
contributed to their unique value as traditional key elements of numerous drugs. In both
lead identification and lead optimization processes, there is an acute need for new small
organic scaffolds.
Nitrogen bridgehead-fused heterocycles containing an imidazole ring are common
structural motifs in pharmacologically important molecules, with activities spanning a
diverse range of targets. Probably, the most widely used heterocyclic system from this
group is imidazo-[l, 2-a] pyridine which contained in marketed drugs such as Zolpidem
(1) benzodiazepine agonist, Olprinone (2) the PDE 3 inhibitor and Zolimidine(3)
antiulcer drug as well as other experimental molecules [3-5].
1 2 3
The heterocyclic compounds play significant role in developing new
antimicrobial, anticancer, antimalarial, anticonvulsant agents. Recent observations
suggested that, heterocyclic compounds containing nitrogen as heteroatom are very
120
CJfA'PTE'lii Imidazo pyridine derivatives containing morpHoRne nucleus
important class of organic heterocycles, because of their wide application in medicine,
agriculture and technology aspects. Among these, 2-phenylimidazo[l,2-a]pyridine
derivatives are of significant synthetic interest due to their diverse range of biological
activities. Some of them showed pharmacological properties such as anti-
inflammatory[6,7],aromatase- inhibitors[8],antibacterial[9],antifungal[10],antiviral[l 1] and
analgesic[12] activities. They have also been shown to be selective cyclin
dependant kinase inhibitors[13], GABA[14], and benzodiazepine receptor agonists[15],
and brady kinin B2 receptor antagonists[16]. The Mannich reaction [17] is an amino
alkylation of an acidic proton with formaldehyde and any primary or secondary amine.
Many literatures reveal that, enhancement of biological activity was found on inclusion
of mannich base into the parent moiety [18-21]. Literature shows the presence of
morpholine moiety in the compounds is act as the building block in the preparation of
Linezolid (4), an antibiotic [22] and anticancer agent [23].
Azole class of drugs particularly fused imidazoles occupy prominent place in
medicinal chemistry because of their broad spectrum pharmacological activities such as
anti-inflammatory, analgesic, anticancer, antimicrobial, antiviral, pesticidal cytotoxicity
and anti-arrhythmic [19-23] activities. Omeprazole, Mebendazole, Pimobendan, and
Albendazole are well known drugs in the market which contain fused imidazole as active
core moiety.
121
CJfAfPEli^ Imidazo pyridine derivatives containing morpHofine nucleus
The insertion of polar groups in the organic molecules leads to change in the
absorption properties of the compound in the body. Cyclic secondary amines like
morpholine are an important class of compounds due to their biological significance in
the field of medicine and agriculture. Morpholines are the key pharmacophores in various
important drugs and biologically significant molecules. Acylation or alkylation of
morpholine enhances the original biological activity of the parent molecule. A number of
N, O substituted morpholines have been found to possess interesting pharmacological
properties. Many morpholine derivatives display varied activities like anti-bacterial, anti
viral, analgesic, anti-inflammatory, as local anesthetics and antiviral agents [24].
Morpholine, a six membered heterocyclic ring is hydrophilic in nature and it
changes the properties of the compound to which it is attached. Morpholine has great
industrial importance and a wide range of applications. It is used as solvent, corrosive
inhibitor and fungicide. The morpholine ring also present in the antidepressant drug
Reboxetine, anticonvulsant like Timonium methyl sulphate. It is also present in some
drugs Pheiunetrazine (7) a stimulant, Morazone (5) a nonsteroidal anti-inflammatory drug
and Fenmetramide (6) an antidepressant drug.
F,C
122
CXA'PT^'R.5 Imidazo pyridine derivatives containing morphoCine nuckus
Desai.C and their co-workers reported the synthesis of a series of novel imidazo-
[l,2-a]pyridine derivatives 8(a-m) and studied their antimicrobial activity [24].
8(a-in)
8(a-i) a= 2-OH; b=2,4 (OH),; c= 4-OH-3-NO;, d=2,4 (OH)2-5-N02; e=3-CI; f=3-Cl-4-F;g= 2-Br; h=3-Br;
i=3-Br-2F; j= 2-Br-4N02; k= 2, 3(F)2, L2,4(F)2; m=2, 6(F)2
Said El Kazzouli et al reported the synthesis of 2-phenylimidazo [1, 2-a]
pyridines (9) as a novel class of melatonin receptor ligands [25].
Miguel Angel and their coworkers synthesized 6-substituted 2-(N-
trifluoroacetylamino) imidazo pyridines (10) and the synthesized compounds were
evaluated for antiproliferative activity against a variety of cancer cell lines. Most of
synthesized compounds displayed moderate cytotoxic activity [26].
R
10
Zhicai Wu and their coworkers designed series of 3, 7-diarylsubstituted
imidazopyridines and developed as a new class of KDR kinase inhibitors. A variety of
123
C3{Jl<PPE1iJ Imidazo pyridine derivatives containing morphoCine nuckus
imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were
identified with good aqueous solubility [27].
o
11 12
Sunil G. Sanghani and Kalpesh J. Ganatra prepared a series of mannich bases (13)
by the reaction of 7-methyl-2-(p-methylphenyl)imidazo[l,2-a]pyridine with secondary
amines and p-formaldehyde in methanol and evaluated them for antimicrobial activities
[28].
,NH2
O »•
AlCIo
CI
N
DM F, Reflux
Methanol
HCHO.Sec Amine
XX^^v^ R-.-
R̂
13
Wesley B Trotter synthesized imidazo morpholine derivatives (14&15) and
studied their analgesic activities [29].
124
CKA<PPE<!i5 Imufazo pyridine derivatives containing morpkoRne nucleus
14 15
Masahiko Hayakawa et al synthesized series of imidazo[l,2-a]pyridine
compounds(16), among which the thiazole derivative inhibited tumor cell growth[30].
-N N
\\ ^ X
R NO,
16
R=CI,X=S02,R =Me
Shrikanth Ulloora et al synthesized series of new imidazo [l,2-a]pyridines(17),
among them many compounds exhibited prominent anticonvulsant activity[31].
17
R=p-CIPh,Ph,p-Tosyl,p-F-Ph,Thiophene-2-
125
CWPM^i Imidazo pyridine derivatives containing morpHofine nucleus
Aldo Andreani et al synthesized imidazo [2, l-b]thiazole guanyl hydrazones(18-
19) which shows potent antitumor activities against breast cancer[32].
N NH2
NH
18 19
Caroline Castera-Ducros et al synthesized series of imidazo [1, 2-a] pyridine
derivatives (20) and evaluated them for antileishmanial activity [33].
20
Ar=2-CH3-C6H4,3-CF3-C6H4,4-OCH3-C6H4
Nurit Dahan-Farkas synthesized 6-substituted imidazo[ 1,2-a]pyridines among
them the following two compounds(21-22) show the proteolytic phase of apoptosis [34].
MeO BnO
OMe
OBn
21 22
Kristjan S. Gudmundsson and Brian A. Johns synthesized imidazo [l,2-a]pyridine
derivatives (23) which shows potent activity against herpes viruses [35].
126
CWPT^'R.S Imidazo pyridine derivatives containing morphoCine nuckus
X=a,Br,H;Y=Me,KC 23
Yoshiyuki Sato, Yu Onozaki synthesized a novel class of imidazopyridines (24)
derivatives which shows antitumor activity [36].
OBz
Said El Kazzouli et al synthesized a novel class of 2-phenylimidazo [1,2-
ajpyridines (25) as melatonin receptor ligands [37].
127
CJfjl'PFEliS Imidazo pyridine derivatives containing morpHoCine nucleus
5.2. Present work
Promoted by the above cited biological importance of imidazo pyridine
derivatives, and in continuation of our efforts to explore biologically important new
heterocyclic compounds, in the present investigation, an attempt was made to improve or
modify its properties to get more potent analogues. The present work describes the
synthesis of series of 4-((2-(4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl) methyl)
morpholine derivatives 29(a-o) by the reaction of substituted imidazo [1,2-a] pyridines
derivatives 28(a-o) with morpholine and formaldehyde.
The synthetic strategy involves the following steps:
1. Synthesis of intermediates substituted imidazo [1,2-a] pyridines derivatives as
reported in chapter 2; 28(a-o)
2. Synthesis of series of 4-((2-(4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl)
methyl) morpholine 29(a-o) derivatives.
The schematic representation of imidazopyridine morpholine derivatives is given in
the following Scheme-6.
128
CJfJl'PI^'R.i Imidazo pyridine derivatives containing morpHoCine nucktis
'XX N NH,
26(a-o)
Comp Rl
a
b
c
d
e
f
g
h
i
J k
1
m
n
0
Br
Br
Br
Br
Br
CH,
CH,
CH,
CH,
CH,
H
H
H
H
H
R2
H
H
H
H
H
H
H
H
H
H
OBz
OBz
OBz
OBz
OBz
R
27
R3
CI
CI
Br
NO,
CN
CI
CI
Br
NO,
CN
CI
CI
Br
NO,
CN
R4
CI
H
H
H
H
CI
H
H
H
H
CI
H
H
H
H
Scheme-6
5.2.1. Synthesis of substituted imidazo [1, 2-a] pyridine derivatives 28(a-o)
Substituted imidazo [1, 2-a] pyridine derivatives 28(a-o) have been synthesized
according to the procedure which is described in chapter 2
129
CKA'PTEliS Imidazo pyridine derivatives containing morphoRne nucleus
5.2.2. Synthesis of 4-((2-(4-chlorophenyl) imidazo [1, 2-a] pyridin-3-yl) methyl) morpholine derivatives 29(a-o).
28(a-o)
H
Q HCHO
EtOH/AcOH
85°C
O - ^ 29(a-o)
The structure of compounds 29(a-o) was confirmed by ' H N M R , '"C N M R and
mass spectral studies. In ' H N M R spectrum, compound 29c showed two triplets at 8 2.41
and 3.52 ppm corresponds to four CH2 protons of morpholine ring and a singlet at 5 4.00
ppm due to bridgehead CH2 protons. The aromatic protons of the compound 29c were
appeared between 8 7.43-8.85ppm. The '^CNMR spectrum of compound 29c showed a
signals at 8 66.0 (2C) and 52 (2C) due to four morpholine carbons, a signal at 8 50.0 ppm
corresponds to methylene carbon and other signals are in well agreement with the
assigned structure. Compound 29c displayed a molecular ion peak M* at m/z 452
corresponding to the molecular mass of the compoimd and isotopic peak [M+2] at m/z
454.
130
Cm<PVE1iS Imidazo pyridine derivatives containing morphoCine nucCeus
I o « O » fJ - -I o c ir o -t
iiiljiiiJ !U
SOS • Z - ^
XEt E —
E a a
* - ' 9 « i .
6:f
i f*
899
itl- L 996' L
^ ^
^
' H N M R spectrum for the compound 29c
131
CJd'PTE'R.S Imidazo pyridine derivatives containing morphotine nucleus
m i •--yfV"-. ¥.1 11. ?^ k!-; 5*1 5f«i
m ih!' £*v;it^. Hi . ^ ^ / Eii-':---
M-.r...l jc: -K" X tfn in->-.' » . i"C! "t?
HI til-'"'
c ft,
- 0
«
I
e i
D n
u§
'•'CNMR spectrum for the compound 29c
132
CXMVEfiS Imidazo pyridine derivatives containing morpHoCine nucleus
Opvniynx R*port Sample' 1 Fle.B OesoiptionB
Vial 2 22 IDS Time 19 48-33
Page
Sample Rapoit
Sample 1 Vial 2:22 ID B File B OeecriptionB
3 : DV DatMStor: TIC
5 .0«+ l i
0 . 0 -
1 . 3 7 8 e + 9»ag»: 1 .378«+
, 0 .50 1 .00 l .SO 2 . 0 0 2 . 5 0 PertNumiier Compound Time AreaAbe Area%Total WMth Height Mace Found
1 142 5e<W6 98.03 0 1e+008 2 153 1e+005 1.97 0 2e+00e
- tuaxii 3 .00
Peak 10 Compound Time Maaa Found 1 142
l:<TijM: 1.42)
lOOn
50-
2 2 6 . 6
I227.6 225 .7v
2 1 4 . 2
\
452.2
365 .1
1367.1
J368.0
454 .2
455.2
200.0 400.0
Peak 10 Compound Time Mas* Found 1 1 4 2
Peak ID Compound Tbne Maae Found 2 1,53
1:MS KS+ 2 : ( T i M : 1 .53) 7.3«+007
2 2 6 . 6 2 2 7 . 6
2 2 5 . 7 ^
100-!
50-
600 .0
214.2, .
I ' > » 1' .|...ii.
3 6 5 . 1
3 6 3 . 1
3 4 7 . 2 J 3 2 1 . 1
4 5 2 . 2
1:H8 E3+ g.eo+ooe
368 l L . 4 5 4 . 1
200.0 400.0 ./« 6 0 0 . 0
l : ( T x : 1 .42)
112 .9 100^
1 50^
\
Peak ID Compound Tktie Ma*« Found 2 1.53
2:M8 SS- 2 : ( I x > a : 1 .53)
= ' ° - * ° " 112 .8 lOOj ^
2:M8 B S -1 .3«+005
488 .0
' 97 .4
o ^ v > ' . ^ .4^tvt, . , f—,., M .^^„-,,/, 200.0 400. 0 6 0 0 . 0
50-j 1 9 6 . 0
O J M U ,
418.2 1 9 9 . 9 3 " - ^ I 4 3 0 . 3
5 2 9 . 1 A
400.0 i/z
6 0 0 . 0
Mass spectrum for the compound 29c
133
CJOt'PFE'R.S Imidazo pyridine derivatives containing morphoRne nucleus
B o. a.
s t i r
$00 Z
t»oz
sjpi
'JXO I oqp. 0661
' H N M R spectrum for the compound 29k
134
C!H'A(PVE<S^5 Imufazo pyridine derivatives containing morpHofine nucleus
i 1 i- -n «r
' ^ CD ^t^ t^ a a a- tx> c as ffi '•^•n E jn •*• r- £7 r
•* -n •* y ; o T »
>
mmmh 1 a* CL< f t t^j ^ I
T9 6£ ^^ , eg 6 C V 4
i t ')V -V
69 3 9 -ZS C i -
=0 >CT—^
CO 6 : i -6C O t t
•3 £»- *C O- k t.» f- -1 I
r cii V o h n {.> a . c h &. :=; t , j r
L 7- (x. t
E Q. a.
OBz
o o CM
"CNMR spectrum for the compound 29k
135
CWPPEliS ImuCazo pyridine derivatives containing morpkoCine nucteus
D«ta f i l «
V i « l Ho.
X n j e c t i o o Date
: D : \ n A T A \ M « . n O \ 8 S 0 1 7 - 1 2 € - n . D
P l - P - 0 3
2 1 / 0 5 / 2 0 1 0
I n j e c t i o n v o l
Acq Mechod
I . O u l
ASCBfTIS CI 8 1IR4
Method i n f o : Method i n £ o : a - 1 0 n N KimaiZVS rCW!<ATX:AC8{98:03} NQBZt.B niSASB B- BOr)nSS:ACN(02:98)
FLOW-1.0«1/Bin Ooluam:ASCRMTIS KXPKE8S CIS SCX2.1IMR 3 .7pm T i a e IB %A
0 0 1 0 0 . 0 l . S 100 0 3 . 2 JOO 0
Mate Ho
1 3 2.207
Area
14.sa« 3154.3S1
Asea %
0.fi8« 99.314
Mass spectrum for the compound 29k
136
CKA'PPE'K.S Imidazo pyridine derivatives containing morpkoRne nucleus
MASS REPORT SYMOefCINTt LTD
nte O.yaATAWAYl»«S0n-l26-17D
ASCSKm Cl« NH4
xlO'
"*f " 1 P H f M B I — M l — » f
Inftrumant: A l̂«al 63J0 loe Tnp
StmHttmnm OefiMtb
A
=.A= 30
•1gH?.<»»"fe"J5iWi
WJ,"',MW^I ..n , , , . 1 . , - ^
"SligjESSSiSi
3-
xlJ^
2,0-
3ML1
4ll,iMr<M
1i!'
Oi>-
Oi> ST- -"isr " ^
?5^
300
ln«lrumantood«:BMS4X}S Analysed Bjr Pagelofl
Mass spectrum for the compound 29k
137
CWPTEIL^ Imidazo pyridine derivatives containing morpHoCine nucleus
5.3. Experimental protocol
5.3.1. Synthesis of substituted imidazo [1,2-a] pyridines derivatives 28(a-o)
General procedure:
An equimolar mixture of substituted-2-aminopyridines 26(a-o) (1 mmol) and
substituted phenacyl bromides 27 (1 mmol) was taken in dry ethanol (10 ml) and the
reaction mixture was refluxed for about 10-12 h at the temperature of 85 °C . Completion
of reaction was checked by TLC. The solvent was distilled off and the content was
poured into crushed ice with uniform stirring. The product separated and filtered, dried
and recrystallized using ethanol. The purification of compound was done by
chromatography on silica gel using ethyl acetate and hexane as an eluent.
6-Bromo-2-(3, 4-dichlorophenyl) imidazo [1, 2-a] pyridine (28a)
m.p.: 155-158°C; ' H - N M R (400MHz, DMSOd*.): 8.88 (s, IH), 8.46 (s, IH), 8.18 (s, IH),
7.94-7.38 (m, 4H, Ar-H); Mol. Formula Ci3H7BrCl2N2
6-Bromo-2-(4-chlorophenyl) imidazo [1, 2-a] pyridine (28b)
m.p.: 168-170°C; ^HNMR (400MHz DMS0d6); 9.18(s, IH), 8.65 (s, IH), 7.99-7.62 (m,
6H, Ar-H); Mol. Formula Ci3H8BrClN2
6-Bromo-2-(4-bromoplienyl) imidazo ]l,2-a] pyridine (28c)
m.p.; 202-204°C; ^HNMR (400MHz DMSO-dg); 9.19 (s, IH), 8.67 (s, IH), 7.91-7.76(m,
6H,Ar-H); Mol. Formula Ci3H8BrClN2
6-Bromo-2-(4-nitrophenyl) imidazo ]1, 2-a] pyridine (28d)
m.p.; 163-165°C; ^HNMR (400MHz DMSO-ds); 9.11 (s, IH), 8.70 (s, IH), 8.17-7.75
(m, 6H, Ar-H); Mol. Formula CnHgBrNsOz
4-(6-Bromoimidazo Jl, 2-a] pyridin-2-yl) benzonitrile (28e)
138
CK^'PT'EliS Imidazo pyridine derivatives containing morphoCine nucleus
m.p.; 175-177°C; ^HNMR(400MHz DMSO-dfc); 9.1 (s, IH), 8.70 (s, IH), 8.37-7.62 (m,
6H, Ar-H), (LCMS): m/z 299 (M+1); Mol. Formula CBHgBrNjOj
2-(3,4-DichlorophenyI)-6-methylimidazo[l,2-a]pyridine(28f)
m.p.; 193-195°C; ^HNMR(400MHzDMSO-d6); 8.85 (s, IH), 8.72 (s, IH), 8.30 (s, IH),
7.98-7.95 (m, 4H, Ar-H), 2.44 (s, 3H); Mol. Formula CMHIOCIJNZ
2-(4-ChIorophenyI)-6-niethylimidazo [1, 2-al pyridine (28g)
m.p.; 188-190°C; ^HNMR (400MHz DMSO-de); 8.77 (s, IH), 8.68 (s, IH), 7.99-7.68
(m, 6H, Ar-H), 2.43(s, 3H). Mol. Formula C14H11CIN2
2-(4-Bromophenyl)-6-methylimidazo [1, 2-a] pyridine (28h)
m.p.; 176-178°C; ^HNMR (400MHz DMSO-ds); 8.743 (s, IH), 8.67 (s, IH), 7.92-7.73
(m, 6H, Ar-H), 2.32 (s, 3H). Mol. Formula CnHnBrNz
2-(4-Nitrophenyl)-6-methylimidazo [1,2-a] pyridine (28i)
m.p.; 191-193°C; ^HNMR (400MHz DMSO-ds); 8.91 (s, IH), 8.73 (s, IH), 8.17-7.81
(m, 6H,Ar-H ), 2.41(s, 3H). Mol. Formula C14H, .Nj O2
4-(6-Methylimidazo [1, 2-a] pyridin-2-yl) benzonitrile (28j)
m.p.; 168-170°C; ^HNMR (400MHz DMSO-dfe); 8.92 (s, IH), 8.73 (s, IH), 8.44-7.77
(m, 6H,Ar-H), 2.42(s, 3H). Mol. Formula CisHnNj
8-(Benzyloxy)-2-(3,4-dichIorophenyl) imidazo [1, 2-a] pyridine (28k)
m.p.; 199-201°C; ^HNMR(400MHzDMSO-d6); 8.84 (s, IH), 8.43-7.27 (m, 10H,Ar-H),
8.33 (s, 1H),5.47 (s, 2H). Mol. Formula CJOHMCIJNZO
8-(Benzyloxy)-2-(4-chlorophenyl) imidazo [1,2-a] pyridine (281)
m.p.; 212-213°C; ^HNMR(400MHz DMSO-ds); 8.83 (s, IH), 8.48-7.34 (m, 12H,Ar-H),
139
CH^'FFE'g^s Imidazo pyridine derivatives containing morpHoCine nucCeus
5.46 (s, 2H). Mol. Formula C20H15CIN2O
8-(Benzyloxy)-2-(4-bromophenyl) imidazo [1,2-a] pyridine (28m)
m.p.; 203-205°C; ^HNMR(400MHz DMSO-de); 8.86 (s, IH), 8.46-7.41(m, 12H,Ar-H),
5.49 (s, 2H). Mol. Formula C2oH,5BrN20
8-(Benzyloxy)-2-(4-nitrophenyl) imidazo [1,2-al pyridine (28n)
m.p.; 177-179°C; ^HNMR (400MHz DMSO-ds); 8.81(s, IH), 8.38-6.9(m, 12H,Ar-H),
5.49 (s, 2H). Mol. Formula C20H15N3O3
4-(8-(Benzyloxy) imidazo [1, 2-a] pyridin-2-yl) benzonitrile (28o)
m.p.; 186-188°C; W M R (400MHz DMSO-de); 8.71 (s, IH), 8.42-7.25 (m, 12H,Ar-H),
, 5.47(s, 2H). Mol. Formula C21H15N3O
5.3.2. Synthesis of substituted 4-((2-phenylimidazo [1, 2-a] pyridin-3- yl) methyl)
morpholine derivatives 29(a-o)
General procedure:
Compounds 28(a-o) (1 mmol), morpholine (1.2mmol), formaldehyde and catalytic
amount of acetic acid was taken in round bottom flask in dry ethanol (8mL) and refluxed for
6-10 hr at 85°C, the progress of the reaction was monitored by TLC. After completion of
reaction, excess of solvent was distilled off and the content was poured into crushed ice
with uniform stirring. The product was separated, filtered, dried and recrystallized using
ethanol. The purification of compound was done by chromatography on silica gel using
a mixture of ethyl acetate and hexane as an eluent.
6-Bromo-2-(3,4-dicIiIorophenyl)-3-(morpholin-4-yImethyl)imidazo[l,2-a]pyridine
(29a)
White solid. Yield- 75 %, m.p. 185-187°C; ' H N M R ( 4 0 0 M H Z DMSO-daSppm): 8.91 (s,
140
CKH^PTEliS Imidazo pyridine derivatives containing morphoCine nucleus
IH), 8.25 (s, IH), 7.93-7.43 (m, 4H,Ar-H), 4.02 (s, 2H), 3.54 (bs, 4H), 2.47 (bs, 4H);
13
CNMR (400MHz D M S O < 8ppm): 145.1, 144.0,136.2, 135.0,133.8, 133.3, 132.5, 132.0,
130.7, 128.8, 127.0, 116.2, 112.1, 66.5, 53.1, 50.5; MS(LCMS):m/z 441[M], 443 (M+2).
Mol. formula; CgHifeBrCbNsO
6-Broino-2-(4-chlorophenyI)-3-(morphoIin-4-yImethyI)iinidazo[l,2-aJpyridine
(29b)
White solid. Yield- 82 %, m.p.l57-159°C; W M R (400MHZ DMS0-d6, 8ppm): 8.84
(s, IH), 7.93-7.42 (m, 6H,Ar-H), 4.01 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^CNMR
(400 MHz DMSO-d6, 8 ppm): 145.0, 144.0, 136.2, 134.3, 135.0, 132.2, 131.3, 129.8,
128.9, 121.3, 66.8, 53.4, 50.3; MS (LCMS): m/z 408 [M+2]; Mol. formula;
CigHnBrCljNjO.
6-Broino-2-(4-bromophenyl)-3-(morpholin-4-yImethyl)iinidazo[l,2-a]pyridine
(29c)
Off white solid, Yield-78 %,m.p.l76-178°C; ^HNMR (400MHz DMSO-dg, 8 ppm):
8.85 (s, IH), 7.86-7.84 (d, 2H), 7.69-7.66 (d, 2H), 7.61-7.59 (d, IH), 7.44-7.41 (d, IH),
4.00 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^C NMR (400MHz DMSO-de. 8 ppm):
145.2, 144.1, 136.2, 135.3, 133.0, 132.4, 129.4, 123.6, 121.3, 66.8, 53.4, 50.6; MS
(LCMS): m/z 451 (M+1), 454 (M+2), Mol. formula; CigHnBrNjO.
6-Bromo-3-(morpholin-4-ylmethyl)-2-(4-nitrophenyl)imidazo[l,2-a]pyridine (29d)
White solid ,Yield- 80 %.m.p.l88-190°C; ^HNMR (400MHz DMSO-de, 8ppm): 8.89 (s,
IH), 8.12 -7.44 (m, 6H, Ar-H), 4.04 (s, 2H), 3.52 (bs, 4H), 2.43 (bs, 4H); ^^C NMR
(400MHz DMSO-d(„ 8ppm): 146, 143, 139, 132, 129, 128, 126, 119, 118, 110, 106,
141
CW^PVE'R^S Imidazo pyridine derivatives containing morpHofine nucEeus
66.7, 52.8, 50.5;MS(LCMS); m/z-416 [M+] Mol.formula;Ci8Hi7BrCl2N403
4-|6-Broino-3-(niorpholin-4-ylmethyl)iniidazo[l,2-a]pyridin-2-yl]beiizonitrile(29e)
White solid,Yield- 74% m.p. 223-225°C; ' H N M R (400MHZ DMSO-de, 8ppm): 8.91 (s,
IH), 8.35-8.33 (m, 6H, Ar-H) 4.07 (s, 2H), 3.53 (bs,4H), 2.45 (bs, 4H); '^C NMR
(400MHz DMSO-dfc. 8 ppm): 145.3, 144.1, 136.6, 135.0, 132.7, 132.5, 132.1, 128.3, 121.4,
116.8, 115.3, 112.4,66.8, 53.2, 50.4; MS(LCMS)-397[M], Mol fomiula; Ci9Hi7BrN40.
2-(3, 4-Dichlorophenyl)-6-methyl-3-(morpholin-4-ylmethyl)imidazo(l,2-
ajpyridine (29f)
Off white solid. Yield- 76 %,m.p. 157-159°C; ^ HNMR (400MHz DMSO-d*, 5ppm):
8.42 (s, IH), 8.28 (s, IH), 7.95- -7.18 (m, 4H), 3.95 (s, 2H), 3.56 (bs, 4H), 2.50 (bs, 4H),
2.35 (s, 3H); '^CNMR (400MHz DMS04. 5ppm): 143, 141, 135, 131.6, 131.1, 130,
128.6, 128.1, 123, 122, 117, 116, 66, 52, 50, 18; MS(LCMS):m/z 376[M].
Mol.formula; C19H19CI2N3O.
2-(4-Chlorophenyl)-6-methyl-3-(morpholin-4-ylmethyl) imidazo[l,2-a]pyridine
(29g)
White solid. Yield- 78% m.p.l39-137°C; ^HNMR (400MHz DMSO-d*. 6ppm): 8.36 (s,
IH), 7.94- 7.15 (m, 6H,Ar-H ) 3.94 (s, IH), 3.53 (bs, 4H), 2.43 (bs, 4H), 2.34 (s, 3H);
^^CNMR (400MHz DMSO-d«. 5 ppm): 143, 142, 139, 132, 130, 129, 128, 123, 121,
117, 116, 67, 53, 21; MS(LCMS)m/z 341[M], Mol formula; C19H20CIN3O.
2-(4-BromophenyI)-6-methyl-3-(iiiorpholiii-4-ylinethyI)imidazo[l^-a]pyridine(29h)
Off white solid. Yield- 76%,m.p. 175-177°C; ^HNMR (400MHz DMSO-d*, 5ppm): 8.37
(s, IH), 7.88- 7.15 (m, 6H,Ar-H), 3.94 (s, IH), 3.53 (bs, 4H), 2.43 (bs, 4H), 2.34 (s.
142
CWPTEli5 Imidazo pyridine derivatives containing morpHofine nucleus
3H); ^^CNMR (400MHz DMSOA 8ppm): 145.2, 144.1, 135.0, 134.3, 133.8, 132.0,
131.9, 129.1, 124.3, 122.1, 66.7, 53.2, 50.5, 24.7; MS (LCMS): m/z 388[M+2], Mol.
Formula; Ci9H2oBrN30.
6-Methyl-3-(morphoIin-4-ylmethyl)-2-(4-mtrophenyl)imidazo[l,2-a]pyridine
(29i)
Pale Yellow solid, Yield-85 % m.p.; 161-163°C; ^HNMR (400MHz DMSOA 8 ppm):
8.41 (s, IH), 8.15-7.19 (m, 6H,Ar-H) 3.98 (s, 2H), 3.32 (bs, 4H), 2.43 (bs, 4H), 2.35 (s,
3H); ^^CNMR (400MHz DMSO-d,, 8ppm): 147.9, 145.4, 144.1, 139.2, 135.0, 134.1,
133.5, 128.4, 124.2, 122.1, 114.6, 66.7, 53.1, 50.4, 24.2; MS (LCMS):m/z 352[M]. Mol
formula C19H20N4O3
4-(6-Methyl-3-(morpholinomethyl) imidazo [1,2-a] pyridin-2-yl) benzonitrile (29j)
Off white solid, Yield- 80%,m.p. 199-203°C; ^HNMR (400MHz DMSO-4, 5 ppm):
8.44 (s, IH), 8.35-7.21 (m, 6H, Ar-H), 4.02 (s, 2H),3.55 (bs, 4H), 2.48 (bs, 4H), 2.36 (s,
3H); ^^CNMR (400MHz DMSO-d«, 5ppm); 145.3, 144.1, 137.3, 135.1, 134.2, 133.6,
132.2, 128.1, 122.2, 115.6, 114.7, 112.2, 66.5, 53.6, 24.4; MS (LCMS): m/z
332[M+]. Mol.formula;C2oH2oN40.
4-((8-(Benzyloxy)-2-(3,4-dichlorophenyl) imidazo [1,2-a] pyridin-3-yl) methyl)
morpholine (29k)
Off white solid,Yield-82 % , m.p. 187-189°C; ^HNMR (400MHz DMSO-d,. 8ppm):
8.22 (s, 2H), 7.92-7.90 (m, 9H, Ar-H),5.33 (s, 2H),3.54 (s, 2H), 3.32 (bs, 4H), 2.44 (bs,
4H); l^CNMR(DMSOd,,8ppm): 147, 140, 139, 136, 135, 31.6, 131.1, 130, 129, 128,
119, 118, 112, 104, 70, 66, 52, 50; MS (LCMS): m/z 468[M+]; Mol. Formula;
143
CWPTEliS Imidazo pyridine derivatives containing morpfioCine nucleus
C25H23CI2N3O2.
4-((8-(Benzyloxy)-2-(4-chIorophenyl) imidazo [1, 2-a] pyridin-3-yI) methyl)
morpholine (291)
Off white solid,Yield-80%,m.p.l78-180°C; ^HNMR (400MHz DMSO-4, 8 ppm): 8.20-
6.8 (m, 12H, Ar-H), 5.32 (s, 2H), 3.95 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^CNMR
(400MHz DMSO4, 8 ppm): 147, 136, 133, 132, 130, 128.9, 128.6, 119, 118, 112, 103,
70, 66, 53, 51; MS(LCMS):m/z 434 (M+1), 436(M+2); Mol formula; C25H24CIN3O2.
4-(8-(Benzyloxy)-2-(4-bromophenyl) imidazo [1,2-a] pyridin-3-yl) methyl)
morpholine (29m)
White solid,Yield-70%, m.p. 224-226°C; ^HNMR (400MHz DMSO-d*, 8ppm): 8.21-6.82
(m, 12H, Ar-H), 5.36 (s, 2H), 3.95 (s, 2H), 3.52 (bs, 4H), 2.41 (bs, 4H); ^^CNMR
(400MHz DMSOdft, 8ppm): 145.3, 143.2, 141.6, 137.1, 135.0, 132.2, 132.1, 129.7, 129.0,
127.7, 127.1, 124.2, 123.1, 70.8, 66.4, 53.8, 50.2; MS(LCMS):m/z 478[M+]; Mol.
formula; C25H24BrN302.
4-((8-(Benzyloxy)-2-(4-iiitrophenyI) imidazo [1,2-a] pyridiii-3-yI) methyl)
morpholine (29n)
Light yellow solid, Yield-72%, m.p. 236-238°C; ^HNMR (400MHz DMSO-4, 6ppm):
8.22-6.83 (m, 12H, Ar-H),5.33 (s, 2H), 3.99 (s, 2H), 3.52 (bs, 4H), 2.43 (bs, 4);
^^CNMR (400MHz DMSOd ,̂ 5ppm): 147.6, 145.3, 143.8, 141.3, 139.1, 137.4, 135.0,
129.0, 128.4, 128.7, 127.9, 124.4, 124.0, 70.8, 65.1, 52.9, 50.6; MS(LCMS): m/z
444[M]. Mol. Formula; C25H24N4O4
144
CWPTEliS Imidazo pyridine derivatives containing morpHofine nucleus
4-(8-(BenzyIoxy)-3-(morphoIinomethyl)imidazo[l,2-a]pyridin-2-yl)benzonitrile
(29o)
Off white solid,Yield-76%,m.p. 203-205°C; Yield-79%; ^HNMR (400MHz DMSO-4,
5ppm): 8.34-6.85 (m, 12H, Ar-H), 5.33 (s, 2H), 4.02 (s, 2H), 3.31 (bs, 4H), 2.45 (bs, 4);
'^CNMR (400MHz DMSOd ,̂ 6ppni): 145.5, 143.4, 141.2, 137.3, 132.5, 129.0, 128.2,
127.7, 127.1, 124.0, 71.0, 66.6, 53.4, 50.8; MS (LCMS): m/z-444 [M+2], Mol.
Formula; C26H24N4O2.
145
CJ&KPTEliS Imidazo pyridine derivatives containing morpHoGne nucleus
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