21
CHAPTER-2
SYNTHESIS OF ARYL UREA DERIVATIVES FROM ARYL AMINES AND
ARYL ISOCYANATES
2.1 INTRODUCTION
The present chapter describes the synthesis of novel diaryl urea
derivatives obtained from aryl amine 1 and aryl isocyanates 2. The
synthesized compounds are analogues of sorafenib [4-{4-[({4-chloro-3(trifluromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine2-carboxamide] .
In the contemporary literature on these functionalized aryl ureas,
phenoxy pyridyl moiety in the final compounds has been modified by
introducing different substituents and chloro-trifluoromethyl phenyl
moiety remains the same. In our strategy, we designed different types of
aryl urea derivatives 3 by replacing chloro and CF3 groups with other
functional variants and synthesized new analogues. The synthetic
scheme for novel analogues of sorafenib is discussed under “Results &
Discussion” (Scheme 2.1).
R1
O
CONHCH3
N
H 2N
R1
Acetone, rt
+
NCO
R2
(1)
O
O
R2
(2)
N
H
N
N
H
(3)
Scheme 2.1
CONHCH3
22
2.2 LITERATURE SURVEY
Due to the important biological activities [74] of substituted ureas,
they are much attracted by researchers. In 1773 the French chemist
H.Rouelle discovered urea in human urine. Urea was synthesized by the
German chemist Friedrich Wohler in 1828 and was the first organic
compound to be synthesized from inorganic starting materials ie..
treating silver isocyanate (AgNCO) with ammonium chloride (NH4Cl). In
1870, urea was produced by heating ammonium carbamate in a sealed
vessel. This was the first time an organic compound was synthesized in
the laboratory from inorganic starting materials, without the involvement
of living organisms. The result of this experiment implicitly discredited
vitalism; the theory that the chemicals of living organisms are
fundamentally different from inanimate matter. This insight was
important
for
the
development
of
organic
chemistry.
Wohler
is
considered by many as The father of modern organic chemistry.
In 1922, the first process was developed for manufacture of urea
by Bosch-Meiser by heating under pressure the mixture of the two gases,
carbon dioxide (CO2) and ammonia (NH3) in about required proportions.
Urea and its derivatives have attracted attention of the chemists
for a long time because of their use in syntheses and useful biological
activities. Some of the substituted ureas having biological activity are
shown below in Table 2.1.
23
Table 2.1
S.No
Compound structure
H3C
1.
Br H
N
H 3C
H
N
O
O
S
H3C
Activity
Acecarbromal
Sedative, hypnotic.
Acetohexamide
Antidiabetic.
Acetylpheneturide
Anticonvulsant.
Aldioxa
Antiulcerative.
Aminoquinuride.
Antiseptic.
N-[(acetylamino)carbonyl]-2bromo-2-ethylbutanamide.
O
N-Acetyl-N-[(cyclohexyl amino)
N
H
N
H
2.
CH3
Common name
O
O
O
IUPAC name
carbonyl]benzenesulfonamide.
O
CH3
H
N
3.
O
H
N
H2N
4.
O
N
O
O
5.
NH2
O
ethyl benzeneacetamide.
Al
OH
[(2,5-Dioxo-4-imidazolidinyl)-
OH
ureato]dihydroxyaluminum.
N
O
N
H
CH3
O
N
H
N
N-[(Acetylamino)carbonyl]-α-
H
N
N, N’-Bis(4-amino-2-methyl-6N
H
NH2
quinolinyl)urea.
24
O
6.
Cl
Cl
N
H
N
N
N,N’-Bis(2-chloroethyl)-N-nitroso
O
F
7.
N
H
Cl
carbonyl]-2,6-
N
H
Lufenuron
Ectoparasiticide.
Nithiazide
Antiprotozoal
Pyriminil
Rodenticide.
N-[[[2,5-Dichloro-4-(1,1,2,3,3,3-
Cl
O
F F
N
H
N
H
H
N
F
hexafluoropropoxy) phenyl]
amino] carbonyl] -2,6-
F
H
N
S
O
O
Cl
O 2N
Insecticide.
difluorobenzamide.
F
8.
Diflubenzuron
N-[[(4-chlorophenyl)amino]
F
CF3
Antineoplastic.
urea.
O
O
Carmustine
diflurobenzamide.
CH3
9.
N-Ethyl-N’-(5-nitro-2-thiazolyl)
N
O
urea.
NO2
O
10.
N
N
H
N
H
N-(4-Nitrophenyl)-N’-(3-pyridinyl
methyl)urea.
25
2-(4-chlorophenoxy)-2-methyl-NO
11.
[[(4-morpholinylmethyl)amino]
O
H3C CH3
Cl
O
N
H
N
H
O
O
O
Sulfaloxic Acid
Anti bacterial.
carbonyl]propanamide.
4’-(carbomoylsulfamoyl)-NN
H
N
H
12.
Antithrombotic
O
S
O
Plafibride
N
OH
(hydroxylmethyl)phthalanilic
N
H
acid.
COOH
H
N
H
N
13.
(H3C)3C
O
N
H
(±)-N-Cyclohexyl-N’-[4-[3-[(1,1Antihypertensive,
dimethylethyl)amino]-2-hydroxy
Talinolol.
O
Antiarrhythmic.
OH
propoxy] phenyl]urea.
[4-{4-[({4-chloro-3-(trifluro meth
14
yl) phenyl]amino} carbonyl)
CF3
Cl
N
H
CONHCH3
O
O
N
H
N
Sorafenib
amino]phenoxy}-Nmethylpyridine-2-carbox amide]
Antineoplastic
26
These observations and our continued interest in the synthesis of anti
neoplastic compounds prompted us to prepare various urea derivatives
as sorafenib analogues.
General preparations of isocyanates:
Richter and Ulrich [75] reported
that the reaction of primary
amines 4 with phosgene (5) leads to chloroformamides 6 which on
heating above 500C eliminate HCl to give isocyanates (7). This useful
reaction constitutes a general method for isocyanate synthesis (Scheme
2.2).
RNH2 + COCl2
2
(4)
-HCl
RNHCOCl
(5)
-HCl
RN=C=O
(6)
(7)
Scheme 2.2
Cotarca et al [76] (Scheme 2.3) reported that triphosgene (8) reacts with
primary
alkyl-and
arylamines
or
their
salts
to
yield
trichloromethylcarbamates 9, which can readily form isocyanates 7. The
existence of trichloromethylcarbamate (9) intermediate as the isocyanate
precursor,
analogoues
to
carbamoyl
chloride
in
the
classical
phosgenation, has been suggested by kinetic and mechanistic studies.
27
-HCl
R-NH2 + Cl3CO-CO-OCCl3
(4)
R-NH-CO-OCCl3
RN=C=O
(9)
(7)
(8)
Scheme 2.3
Staab and his co workers [77] (Scheme 2.4) reported that primary
imidazole-N-carboxamides (11) are obtained from primary amines (4)
and carbonyl diimidazole (10) are dissociated into isocyanates (7) and
imidazole (12), even at room temperature. This dissociation forms the
basis for a simple method of preparing isocyanates from aliphatic,
alicyclic and aromatic amines.
O
R-NH2 + N
(4)
N
(10)
O
N
N
THF
N
N
20oC,
RHN
N
(11)
N
RN=C=O +
+
N
H
(12)
(7)
Scheme 2.4
According to Stern and Spector [78] (Scheme 2.5), primary aliphatic or
aromatic amines react with carbon monoxide in the presence of PdCl2.
The reaction proceeds readily under mild conditions and is accompanied
by reduction of PdCl2 to palladium metal.
N
H
(12)
28
RN=C=O + Pd + 2HCl
RNH2 + CO + PdCl2
(4)
(7)
Scheme 2.5
Carbonylation of aromatic nitroso compounds 13 were reported by
Unverferth et al [79] (Scheme 2.6) by using rhodium and iridium
carbonyls.
RN=C=O + CO2
RNO2 + 2CO
(13)
(7)
Scheme 2.6
General prepartions of urea derivatives:-
The simplest and direct synthesis of substituted ureas is described
by Shriner et al [80] (Scheme 2.7).
O
X'
X
(14)
O
RNH2
-HX
RNCO
RHN
X'
-HX'
(15)
(7)
R'NH2
R'NH2
O
RHN
NR'H
(16)
Scheme 2.7
29
The process essentially involves two steps; (i) reaction of the selected
amine with the reagent 14 containing the carbonyl group to form the
intermediate 15 still possessing a leaving group linked to the cabonyl; (ii)
further reaction of the intermediate 15 with the same amine or with a
different
amine
to
form
the
symmetrical
or
the
unsymmetrical
substituted urea 16 directly or through the more reactive isocyanate 7.
Izdebski and Pawlak [81] reported that bis (4-nitrophenyl) carbonate
(17), a very stable reagent can be converted into carbamates (18) (4478% yield) by reaction with equimolecular amounts of primary aliphatic
or aromatic amines within 2h in dichloromethane. The carbamate
intermediates 18 react further with different primary amines giving rise
to the unsymmetrical ureas 16 in good yields (scheme 2.8). The second
step is considerably slower than the first and requires a longer reaction
time of ca. 4h necessitating reacting 17 with an excess of amine (1:2
ratio).
O
O
O2N
O
(17)
H
RNH2
R
NO2
O
N
R'NH2
O
RHN
O
NR'H
NO2
(18)
(16)
Scheme 2.8
One application is reported by Lamothe et al [82] (Scheme 2.9) for ditert-butyldicarbonate (19) [(BOC)2O], a well-known reagent utilised for
protecting the amino group giving N-BOC-primary amines (20) with high
30
yield
and
selectivity.
The
reagent
can
20
be
converted
into
unsymmetrically substituted ureas 16 by reaction with a second amine.
The reaction requires the use of strong bases such as alkyllithiums,
which convert 20 into the isocyanate 7 capable of undergoing fast
addition of a second amine affording the final unsymmetrical urea 16.
O
Bu'O
OBu'
O
O
RNH2
BuLi
R N
OBu'
R N
Li
H
(19)
OBu'
(20)
(21)
-Bu'OLi
O
R
N
N
H
H
(16)
R'
R'NH2
RNCO
(7)
Scheme 2.9
Batey et. al [83] (Scheme 2.10) reported that N,Nl-carbonyldiimidazole
(22) (CDI) is utilized as starting reagent for the general synthesis of
unsymmetrical tetra substituted ureas. The intermediate carbonyl
imidazole 23 is first obtained by reaction of CDI with a secondary amine.
Compound 23 is successively converted into the more reactive and
resonance-stabilized imidazolinium salt 24 by N-alkylation of the
imidazole moiety. Addition of a different secondary amine to 24 furnishes
N, N, N', N'-unsymmetrical tetrasubstituted ureas (25) in high yield
(Scheme 2.10).
31
O
N
O
RR'NH
N
R
N
N
O
MeI
N
N
R'
R
N
N
O
R''R'''NH
N
R'
N+
I-
(22)
(23)
R
Et3N
N
R'
R'''
Me
(24)
(25)
Scheme 2.10
In a similar way Katritzky [84] (Scheme 2.11) and his co-workers
reported that N, N'-carbonyldibenzotriazole (26) can be utilized to
synthesise N, N, N', N'-unsymmetrical tetra substituted ureas (25) by
one-pot
reaction
with
the
first
amine
to
produce
the
carbonyl
benzotriazole intermediate 27 that can react under more forceful
conditions with a second amine giving the final urea 25 in satisfactory to
good yield.
N
N N
O
O
O
N
N N
(26)
RR'NH
R
R''R'''NH
N
N
R'
N N
(27)
R
R''
N
N
R'
R'''
(25)
Scheme 2.11
Thavonekham [85] reported that disubstituted ureas 16 including some
chiral compounds are efficiently synthesized by reaction of amines with
carbamates 29, which in turn are prepared from phenyl chloroformate
(28) (Scheme 2.12)
R''
N
32
O
Ph
O
O
RNH2
Cl
Ph
DMSO
(28)
O
R'NH2
O
NHR
NHR
R'HN
DMSO
(29)
(16)
Scheme 2.12
The
synthesis
carbonylation
of
of
N,
lithium
N,
N',
amides
N'-tetrasubstitutedureas
30
with
carbon
31
by
monoxide
at
atmospheric pressure under mild conditions has been reported by
Nudelman et al [86] (Scheme 2.13) The advantages of this method are
the short reaction time and use of molecular oxygen as oxidant.
R'
R
N
R'
CO
Li
R
Li
N
R
O
R'
R'
N
N
LiO
OLi
(30)
O2
R
R
R'
R'
N
N
O
(31)
Scheme 2.13
Nomura and his co-workers [87] (Scheme 2.14) reported that the
catalyst Ph3SbO/P4S10 utilised in the molar ratio amine/ Ph3SbO/P4S10
40/1.0/2.0 is highly effective for the carbonylation of both amines and
diamines giving linear and cyclic ureas at 80-150oC for 12h with CO2.
Monitoring the reaction by
13C
NMR spectroscopy revealed that the
reaction course constitutes thiolation of the carbamic acid 32 to an
R
33
intermediate antimony carbamate species followed by aminolosis of the
carbamothioic acid thus formed.
H
RNH2
CO2
R
H
OH
N
O
(4)
RNH2
R
N
Ph3SbO/P4S10
S NH2R
Ph3SbO
R
O
H
H
N
N
R
O
(32)
(33)
Scheme 2.14
McGhee et al [88] (Scheme 2.15) reported that carbamate esters
34 could be synthesized by reaction of amines with carbon dioxide and
alkyl halides in the presence of bases.
RNH2
H
CO2/base
R"Cl
R
OR"
N
R'NH2
O
(4)
(34)
R
H
H
N
N
R'
O
(16)
Scheme 2.15
2.3 PRESENT WORK
The present chapter describes the design and preparation of a
series of aryl ureas as novel analogues of sorafenib and their
characterization aspects. The novel analogues of sorafenib of present
work consist of urea derivatives having functional variants in the aryl
fragment other than the phenoxy pyridyl moiety.
34
The analogues of sorafenib [4-{4-[({4-chloro-3-(trifluoromethyl)
phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2carboxamide] are designated as 3a - 3o and the synthetic scheme for the
preparation of these compounds is depicted in Scheme 2.1
The process consists of coupling of amine 1 and isocyanate 2 in
acetone medium at room temperature to afford the required product in
good yield and purity. The Physico-chemical properties of the synthesized
analogues of sorafenib are described in experimental section. The key
intermediates, isocyanates 2, were prepared from the reaction of
triphosgene (8) and appropriate amine 35 in methylene chloride at reflux
temperature (Scheme 2.16)
R1
R1
(8)
NH2
R2
CH2Cl2, reflux
(35)
NCO
R2
(2)
Scheme2.16
Purity of isocyanates was estimated by HPLC via derivatization to
methyl carbamates due to the inherent instability of isocyanates. Yield
and purity of the synthesized isocyanates are given in experimental
section.
35
The intermediate 4-(2-(N-methyl carbamoyl)-4-pyridyloxy) aniline
(1) has been prepared from the known process [89] in three steps from 2picolinicacid (36) as shown below (Scheme 2.17).
Cl
Cl
SOCl2
N
CO2H
aq.CH3NH2
MeOH
70-75oC
N
HCl
5-10oC
N
COOCH3
.HCl
COCl
(36)
(37)
Cl
N
OH (39)
H2N
CONHCH3
O
Potassium t-butoxide
80-90oC, 2-3h
CONHCH3
N
H2N
(38)
(1)
Scheme 2.17
2.4 DOCKING STUDIES
We
proposed
total
fifteen
analogs
of
sorafenib
and
these
compounds were screened by molecular docking using Computer-Aided
Drug Design (CADD) technique to design sorafenib analogues based on
structure based drug designing studies.
CADD is an existing and diverse discipline where different aspects
of applied and basic research merge and stimulate each other [90]. All
the world’s major pharmaceutical and biotechnology companies use
computational design tools.
The growing number of chemical and
biological databases and an explosion in currently available software
tools are providing a much-improved basis for design of ligands and
inhibitors with desired specificity. The phrase Computer-Aided Drug
36
Design implies that drug discovery lies in the hands of computational
scientists who are able to manipulate molecules on their computer
screens [91]. The drug discovery process is actually a complex and
interactive one, involving scientists from many disciplines working
together to provide many types of information.
To evaluate the docking study of above series of compounds by
CADD, we employed 1UWH from protein data bank (PDB) ID [92]. 1UWH
is the protein responsible for kinase inhibitors. The docking study of
novel analogues of sorafenib of current work was carried out along with
sorafenib as reference molecule.
Docking Studies of sorafenib Analogues
Computational Details
The Docking process was carried out by using Ligandfit program of
Discovery Studio2.1 [93]. Software validation was performed in ligandfit
using PDB protein 1UWH[94]. To ensure that the ligand orientation and
the position obtained from the docking studies were likely to represent
valid
and
reasonable
binding
modes
of
the
inhibitors,
docking
parameters had to be first validated for the crystal structure used PDB
ID –1UWH[94].
The ligand sorafenib found in the crystal structure, was extracted and
docked back to the corresponding binding pocket, to determine the
ability of Docking method to reproduce the orientation and position of
the inhibitor observed in the crystal structure.
37
Molecular Docking
To gain better insight for interaction between various compounds
and target, Ligandfit program was employed to dock the designed list of
sorafenib analogues. Ligandfit program requires molecules in sd, mol or
mol2 format. All given structures were prepared by using Prepare Ligand
program. For each run, maximum of 20,000 Monte Carlo run was used
in the docking experiment. The distance for hydrogen bonding was set at
2.5 Å. All docking runs were performed by using PLP force field [95-96].
Details of docking study of the novel analogues of sorafenib of current
work are tabulated in the Table 2.2.
Scoring functions
The docked conformations were further scored using different
scoring functions available with Ligandfit. The LigandFit algorithm uses
an internal scoring function, DockScore, to select and return dissimilar
poses for each compound. DockScore is a simple force field based scoring
function, which estimates the energy of interaction by summing the
ligand/protein interaction energy and the internal energy of the ligand.
CFF force field was used to resolve the van der Waals parameters for
DockScore. The top DockScore pose was used for post docking scoring.
Scoring was performed using a set of scoring functions as implemented
in Ligandfit. These included LigScore1, LigScore2, PLP1, PLP2 and
DockScore available from the docking process [97]. The putative 3D
poses and score results were then stored as an SD file.
38
Table 2.2 - Scoring table
Molecule
PLP1
PLP2
DOCK
Lig 2
Sorafenib
153.93
141.33
133.92
7.82
3a
134.61
130.2
124.22
7.62
3b
132.13
122.53
118.086
7.35
3c
110.74
105.75
116.221
6.99
3d
158.2
142.73
133.79
7.9
3e
132.5
123.04
122.54
7.44
3f
136.88
124.34
119.31
7.05
3g
140.07
128.01
130.25
7.63
3h
133.39
126.86
122.21
7.22
3I
131.92
123.15
121.993
7.23
3j
128.05
126.39
119.753
7.04
3k
128.42
122.3
119.49
6.72
3l
138.66
131.1
13.917
7.81
3m
136.56
129.39
125.889
7.78
3n
132.53
123.7
118.32
6.61
3o
140.25
128.78
125.58
7.61
Docking pictures
Super imposed structures of the docked molecules with reference
molecule are given below.
39
Superimposed structure of 3 d (grey) with sorafenib (yellow)
H-bond interaction of 3d with B-Raf protein (PDB ID –1UWH)
Represented as green dots.
40
Superimposed structure of 3m (grey) with Sorafenib (yellow)
H-bond interaction of 3m with B-Raf protein (PDB ID –1UWH)
represented as green dots.
41
Superimposed structure of 3o(grey) with Sorafenib (yellow)
H-bond interaction of 3o with B-Raf protein (PDB ID –1UWH)
Novel analogues of sorafenib of present work are designated as 3 (a-o).
42
Docking Results
According to docking studies which is based on binding affinity, Hbond interaction and scoring value, it was revealed that out of fifteen
docked analogues four compounds 3d, 3g, 3m, and 3o are found to be
good fits in terms of the docking scores.
2.5 RESULTS AND DISCUSSION
The primary amine, 4-nitroaniline (35o, ie 35, R1=4-NO2, R2=H)
on reaction with triphosgene (Cl3CO-CO-OCCl3, 8) in dichloromethane at
reflux temperature gave 4-nitrophenyl isocyanate (2o, ie 2, R1=4-NO2,
R2=H), which is characterized on the basis of spectral data (Scheme
2.16). Thus, its IR (neat) (Fig. 2.1) showed a very sharp band of strong
intensity in the region 2262cm-1 assignable to –N=C=O stretching and
absence of amine (35) -NH2 peaks at the 3481 and 3360cm-1 indicating
the complete conversion of amine to isocyanate. Its
1H
NMR (CDCl3
/TMS) (Fig. 2.2) showed signals at δ 7.24(d, J= 8.8, 2H aryl protons); δ
8.22 (d, J = 8.8, 2H aryl protons). The
13C
NMR spectrum of 4-
nitrophenyl isocyanate (Fig. 2.3) exhibited that the aromatic carbon
atoms from δ 125.2 to 140 ppm. The isocyanate carbon resonates at
about δ145ppm. The mass spectrum (CI method) of this compound (2o)
has shown the molecular ion peak at 163.9 (Fig 2.4) as base peak. The
fragment ion at 136.84 shown the loss of neutral molecule, carbon
monoxide from the product.
43
R1
R1
(8)
NH2
R2
CH2Cl2, reflux
NCO
R2
(35)
(2)
Scheme 2.16
Entry R1
R2
Entry R1
R2
a
4-Br
H
i
2-Me
4-Me
b
2-Cl
H
j
2-Me
5-Me
c
2-Cl
6-Me
k
2-Me
6-Me
d
4-Cl-3-CF3
6-NO2
l
3-Me
4-Me
e
4-F
H
m
3-Me
5-Me
f
4-F
2-NO2
n
3-NO2
H
g
3-CF3
H
o
4-NO2
H
h
2-Me
3-Me
The above reaction was found to be a general one and has been
observed to be facile with a variety of arylamines 35 as tabulated above.
The structures of the isocyanate products 2, thus obtained were
confirmed on the basis of spectral and analytical data (Experimental
Section).
2-Picolinic acid (36) was reacted with thionyl chloride in toluene
medium at 70-75 ºC to obtain 4-chloropicolinyl chloride hydrochloride.
This acid chloride, when reacted in situ with methanol, afforded methyl
4-chloro-2-picolinate hydrochloride (37). The IR spectrum showed ester
44
carbonyl peak at 1742 cm-1shifted from acid carbonyl peak at 1718 cm-1
and absence of O-H str peak at about 3100 cm-1. The compound 37 on
reaction with aqueous methylamine in toluene gave 4-chloro-N-methyl-2pyridine carboxamide (38). Its IR spectrum exhibited the amide carbonyl
peak at 1686 cm-1. 38 was reacted with 4-aminophenol (39) in DMF in
the presence of potassium t-butoxide at 80 ºC to afforded the ether
derivative, 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (1), which has
been characterized by its spectral data. Thus, its IR spectrum showed
amide carbonyl peak with sharp and strong intensity at1658 cm-1. Sharp
peak with medium intensity at 3337 cm-1 assignable to N-H str. Its 1H
NMR (DMSO) showed signals at δ 2.77(d, J=4.7, 3H) assignable to methyl
protons, δ 5.1 (s, 2H) assignable to NH2 protons. The aromatic protons
appeared in the aromatic region at about δ 8.0. Its Mass spectrum (ESI,
m/z) showed the [M+H]+ ion peak at 244 corresponding to the molecular
mass of 243 (Scheme 2.17).
Treatment of 1 with 2-Chloro-6-methylphenylisocyanate (2c) in
acetone medium for 3-4h at 40 ºC afforded the aryl urea derivative of
Sorafenib
analog,
4-{4-[({2-Chloro-6-methyl}phenyl)amino}carbonyl)
amino]phenoxy}-N-methylpyridine-2-carboxamide
(3c)
(Scheme2.1),
which has been characterized on the basis of spectral and other
analytical data. The IR (KBr) spectrum (Fig. 2.5) of 3c showed sharp
peaks at 3403 cm-1 and at 3296 cm-1 corresponding two NH absorptions
of urea derivative. And showed amide C=O str band at 1687 cm-1. The
45
urea carbonyl peak observed at 1646 cm-1. Its 1H NMR spectrum (CDCl3
/TMS) (Fig. 2.6) showed signal at δ 2.28(s, 3H, -NHCH3), at δ 2.79(s, 3H,
aryl CH3), δ 7.1-7.3 (complex m, 7H, two aryl and three pyridyl ring
protons), δ 7.6(d, J=8.88, 2H, aryl protons), δ 8.02 (s, 1H, D2O
exchangeable -NH-), δ 8.5 (d, J=5.6,1H, aryl proton), δ 8.8(d, 1H, J=4.8) δ
9.08(s, 1H, D2O exchangeable -NH-). Its
13C
NMR (400MHZ, DMSO d6)
spectrum (Fig. 2.7) showed signals at δ 18.74(Ar-CH3), 26.22(-NH-CH3),
108.91, 114.15, 119.90, 120.00, 121.67, 127.05, 127.59, 129.32,
132.12, 134.02, 138.03, 138.85, 147.54, 150.60, 152.52, 153.09,
164.17(-N-CO-), 166.28(-N-CO-N-). Its Mass spectrum (ESI, m/z) (Fig.
2.8) showed the [M+H]+ ion peak at 411 corresponding to the molecular
mass of 410. Fig 2.9, Fig 2.10 showed HPLC chromatograms of 3c and
3d respectively.
R1
R1
O
CONHCH3
+
N
NCO H2N
R2
(2)
O
O
Acetone, rt
R2
(1)
N
H
CONHCH3
N
N
H
(3)
Scheme 2.1
The above reaction was found to be a general one and has been
found to lead to other derivatives of 3 [3a to 3o]. The structures of the
products 3, thus obtained were confirmed on the basis of spectral data
(Experimental Section).
46
Scheme for the formation of isocyanates as given below:-
heating
3COCl2
Cl3CO-CO-OCCl3
(8)
(5)
COCl2 +
RN=C=O + 2HCl
RNH2
(5)
(4)
(7)
Possible mechanism for the formation of aryl urea derivatives as
given below:-
H
N + R'
R
H
H
N
C
O
R
H
+
N
C
O
H
N
R'
R
H
R
N
H
O
N
R'
O
R
=
H 2N
+
C
H
CONHCH3
N
R
N
C
O
N
H
R'
N
C
..
O
N
R'
H
47
2.6 EXPERIMENTAL SECTION
37 [98]: To a stirred solution of thionylchloride (483g, 4.0mole) and DMF
(10ml) was added 36 (100g, 0.81mole) in lots at 40-45 ºC. The reaction
mass was maintained at 70-75 ºC for 16h. Excess thionyl chloride was
distilled off keeping the mass temperature at 75-80 ºC. Finally toluene
(2x200ml) was added and the mixture co-distilled to remove toluene
along with traces of thionyl chloride. The reaction mass was cooled and
added to pre cooled (0-5 ºC) mixture of toluene (100ml) and methanol
(39ml). The reaction mass was maintained at 0-10 ºC for 2h and filtered.
The solid mass was washed with toluene (100ml) and chilled (5-10 ºC)
acetone (250ml). The material was dried at 60-65 ºC for 1-2h to get the
methyl 4-chloro-2-picolinate hydrochloride (37, 121g) and directly used
for further work.
38: To a stirred solution of aq. methylamine (124.1g, 4.0mole) in toluene
(200ml) was added 37 (115g, 0.56mole) in lots below 5 ºC within 3045min. The reaction mass was maintained at 5-10 ºC for 2h. Aliquots
were followed by TLC. After completion of the reaction, the mixture was
allowed to cool to room temperature and extracted with toluene
(3x200ml). The toluene layer was washed with saturated sodium chloride
solution (5%, 2x200ml). Carbon treatment was given for the toluene
layer. Toluene was distilled off at 75-85 ºC using rotavapour to obtain the
residue of 38 (94.3g). This material was used for further work.
48
1: To a stirred solution of 39 (38.4g, 0.35moles) in DMF (280ml) was
added potassium t-butoxide (41.4g, mole) in lots keeping the mass
temperature below 40 ºC under nitrogen atmosphere. The reaction was
maintained at 25-30 ºC for 2h. A solution of 38 (50.0g, 0.25mole)
obtained from the above reaction) in DMF (50ml) was added to the
reaction mass. Potassium carbonate (22.3g) and potassium iodide (2.5g)
were added in succession to the reaction mass. The reaction mass was
maintained at 80-90 ºC for 2-3h. Aliquots were followed by TLC. After
completion of the reaction by TLC, reaction mass was cooled to room
temperature.
The reaction mass was poured into DM water (1.0L)
keeping the mass temperature 25-30 ºC. The product was extracted with
toluene (4x500ml) and the toluene layer was washed with 5% aq.sodium
hydroxide solution (2x400ml) until absence of 39 was indicated in the
toluene layer. Carbon treatment was given for toluene layer at 70-80 ºC.
The filtrate was concentrated under vacuum at 75-85ºC, the residue was
cooled to –5 to 5 ºC under stirring and maintained for 45-60min. The
reaction was filtered and washed the wet solid with chilled (0-5 ºC)
toluene (100ml). The wet material (59.5g) was dried in the oven at 60-65
ºC
for 2h (till constant wt is obtained) to obtain the product 1 (57.5g). The
purity (HPLC) of this material was checked and used for further work.
49
General procedure for the preparation of isocyanates (2):
To
a
stirred
solution
of
the
amine
(35,
0.01mole)
in
dichloromethane (50ml) was added 8 (0.005mole) in lots at 15-20 ºC. The
condenser was provided with cold water circulation during the addition
of 8, and carbon (1.0g) was added to the reaction mass. The reaction
mass was maintained at room temperature for 2h, raised to reflux and
maintained for 5-6h. Aliquots were followed by IR for confirmation of
isocyanate formation by observing the peak at 2250-2275 cm-1 and
absence of characteristic peak of primary amine at about 3200 cm-1.
After completion of the reaction by IR, the reaction mass was cooled and
filtered. Then filtrate was concentrated under reduced pressure. Finally,
the residual mass was azeotroped with toluene (3x10ml) under vacuum
to remove the traces of 8. The obtained crude aryl isocyanate 2 was
dissolved in acetone and taken to next step.
2a). (i.e., 2, R1 = 4-Br, R2 = H). Yield 1.7g (85%). Purity (HPLC): 95%. IR
(neat, cm-1): 2273 (–N=C=O vib), 1618, 1520, 1457, 1049, 736.
1H-NMR
(400MHz, CDCl3) δ: 7.22 (d, J=10, 2H, Ar-H), δ: 7.76 (d, J=10.8,
2H, Ar-H).
2b). (i.e., 2, R1 = 2-Cl, R2 = H) yield1.33g (87%). Purity (HPLC): 93%. IR
(neat, cm-1): 2257 (–N=C=O vib), 1646, 1591, 1517, 1450, 1053, 751.
1H-NMR
(400MHz, CDCl3) δ: 7.29-7.53 (complex m, 4H, Ar-H)
50
2c). (i.e., 2, R1 = 2-Cl, R2 = 6-Me) Yield 1.67g(91%.) Purity (HPLC): 97%.
IR (neat, cm-1): 2270 (–N=C=O vib), 1601, 1519, 1470, 1047, 764.
1H-NMR
(400MHz, CDCl3) δ: 2.34 (s, 3H, -CH3), 7.19-7.55 (complex m,
3H, Ar-H)
2d). (i.e., 2, R1 = 4-Cl-3-CF3, R2 = 6-nitro) Yield 1.82g (68%). Purity
(HPLC): 89%. IR (neat, cm-1): 2274 (–N=C=O vib), 1625, 1577, 1527,
1369, 1345, 1304, 1263, 1152, 909, 827, 761.
1H-NMR
(400MHz, CDCl3) δ: 7.92(s, 1H, Ar-H), 8.23 (d, J=9.6 Ar-H).
2e). (i.e., 2, R1= 4-F, R2 = H) Yield 1.25g (92%). Purity (HPLC): 91%. IR
(neat, cm-1): 2280(–N=C=O vib), 1735, 1522, 1231, 1151, 1094, 1014,
834.
1H-NMR
(400MHz, CDCl3) δ: 7.29-7.36 (complex m, 4H, Ar-H).
2f) (i.e., 2, R1= 4-F, R2 = 2-NO2) Yield 1.82g (86%). Purity (HPLC): 93%.
IR (neat, cm-1): 3472, 3356, 3096, 2267 (–N=C=O vib), 1730, 1543, 1342,
1132, 944, 879, 814, 731, 565.
1H-NMR
(400MHz, CDCl3) δ: 7.62-8.23 (complex m, 3H, Ar-H).
2g). (i.e., 2, R1 = 3-CF3, R2 = H) Yield 1.74g(94%). Purity (HPLC): 92%.
IR (neat, cm-1): 2270(–N=C=O vib), 1617, 1596, 1325, 1179, 1134, 1067,
944, 820, 696, 525.
51
1H-NMR
(400MHz, CDCl3) δ: 7.27-7.29(complex m, 1H, Ar-H), 7.35 (bs.
1H, Ar-H), 7.46 (d, J=4.8, 2H, Ar-H), MS (ES): 186 [M-1]
13C-NMR:
δ 121.6, 122.48, 124.73, 125.23, 128.03, 130.16, 132.2,
134.28.
MS (CI): m/z 186 [M-H]+.
2h). (i.e., 2, R1 = 2-Me, R2 = 3-Me) Yield1.37g (93%). Purity (HPLC): 97%.
IR (neat, cm-1): 2272 (–N=C=O vib), 1705, 1499, 1086, 864, 776, 566.
1H-NMR
(400MHz, CDCl3) δ: 2.37(s, 6H, 2x CH3), 6.9 (d, J=8.4, 1H, Ar-
H), 7.21-7.34 (m, 2H, Ar-H).
2i). (i.e., 2, R1 = 2-Me, R2 = 4-Me) Yield1.35g (92%). Purity (HPLC): 98%.
IR (neat, cm-1): 2278 (–N=C=O vib), 1756, 1521, 1080, 814, 562.
1H-NMR
(400MHz, CDCl3) δ: 2.34 (s, 6H, 2x CH3), 6.93 (d, J=8.8, 1H, Ar-
H), 7.02 -7.18 (m, 2H, Ar-H).
2j). (i.e., 2, R1 = 2-Me, R2 = 5-Me) Yield1.33g (91%). Purity (HPLC): 97%.
IR (neat, cm-1): 2922, 2273(–N=C=O vib), 1617, 1518, 1079, 810, 559.
1H-NMR
(400MHz, CDCl3) δ: 2.28 (d, J=2.8, 6H, 2x CH3), 6.88-7.25
(complex, m, 3H, Ar-H).
13C-NMR:
δ 17.57, 20.47, 125.39, 126.45,
128.09, 128.90, 129.47, 131.93, 136.62; MS (ES); MS (CI): m/z 147(M)+.
52
2k). (i.e., 2, R1 = 2-Me, R2 = 6-Me) Yield 1.4g (95%). Purity (HPLC): 99%.
IR (neat, cm-1): 2919, 2275(–N=C=O vib), 1609, 1510, 845, 571.
1H-NMR
(400MHz, CDCl3) δ: 2.36 (s, 6H, 2x CH3), 7.04-7.43 (complex m,
3H, Ar-H).
2l). (i.e., 2, R1 = 3-Me, R2 = 4-Me) Yield 1.38g(94%). Purity (HPLC): 94%.
IR (neat, cm-1): 2918, 2269(–N=C=O vib), 1607, 899, 839, 567. 7.08-7.26
(m, 3H, Ar-H).
1H-NMR
(400MHz, CDCl3) δ: 2.28(s, 6H, 2x CH3), 6.7 (s, 2H, Ar-H), 7.41
(s, 1H, Ar-H).
2m). (i.e., 2, R1= 3-Me, R2 = 5-Me) Yield 1.32g (90%). Purity (HPLC):
92%.
IR (neat, cm-1): 2921, 2266(–N=C=O vib), 1609, 900, 843, 682, 551.
1H-NMR
(400MHz, CDCl3) δ: 2.32 (s, 6H, 2x CH3), 6.9 (s, 2H, Ar-H), 7.16
(bs, 1H, Ar-H).
2n). (i.e., 2, R1 = 3-NO2, R2 = H)Yield 1.44g (88%). Purity (HPLC): 89%.
IR (neat, cm-1): 2269 (–N=C=O vib), 1594, 1515, 1340, 847, 753.
1H-NMR
(400MHz, CDCl3) δ: 7.42-8.0 (complex m, 4H, Ar-H).
2o). (i.e., 2, R1 = 3-NO2, R2 = H) Yield 1.32g (79%). Purity (HPLC): 96%.
IR (neat, cm-1): 2262 (–N=C=O vib), 1596, 1518, 1344, 855, 749.
1H-NMR
(400MHz, CDCl3) δ: 6.93 (d, J=10.8, 2H, Ar-H), 8.14 (d, J=10.4,
2H, Ar-H)
53
General procedure for the preparation of urea derivative (3):
To a stirred solution of 1 (0.01mole) in acetone (50ml) was added 2
(0.01mole) in acetone (10ml) keeping the temperature below 40 ºC. The
reaction mass was maitained at room temperature for 3-4 h followed by
TLC. After completion of reaction the product was filtered from the
reaction mass, washed with acetone (5ml) and dried at 60-65 ºC for 2h to
obtain crude 3.
3a). (i.e., 3, R1 = 4-Br, R2 = H). Yield 4.14g (94%). Pure 3a (Acetone).
M.F: C20H17BrN4O3; Purity (HPLC): 97.5%; m.p: 229.6 ºC. HCl salt : 192.6
ºC;
PTs salt :145.2 ºC.
IR (KBr, cm-1): 3391, 3256, 1677, 1654, 15931545, 1538, 1504, 1487,
1463, 1406, 1391, 1296, 1222, 1199, 1073, 993, 928, 828, 785, 766,
556, 505.
1H-NMR
(400MHz, DMSO d6) δ: 8.91(s, 2H), 8.79 (d, J=4.8 1H), 8.51(d,
J=5.6 1H), 7.58 (d, J=8.8 2H), 7.46 (s, 4H), 7.38 (d, J=2.4 1H), 7.18 (m,
3H); 2.80 (d, 3H).
13C
NMR (DMSO d6) δ (ppm): 26.04, 108.72, 113.31, 113.96, 120.11,
120.18, 121.47, 131.53, 137.42, 139.12, 147.56, 150.29, 152.40,
152.47, 1638, 166.04;
MS (CI): m/z 443.4 [M+2H]+.
54
3b). (i.e., 3, R1 = 2-Cl, R2 = H) yield 3.83g (97%). Pure 3b (Acetone).
Purity (HPLC): 99.2%; M.F: C20H17ClN4O3; m.p: 213.8 ºC. HCl salt: 150.0
ºC;
PTs salt: 146.5 ºC.
IR (KBr, cm-1): 3296, 1687, 1646, 1591, 1560, 1530, 1505, 1471, 1441,
1407, 1297, 1222, 922, 847, 739.
1H-NMR
(400MHz, CDCl3) δ: 8.55 (s, 1H, exch with D2O); 8.42 (d, J=5.6
1H), 8.26-8.28 (dd, 2H), 7.66(d, J=19.6 2H), 7.45 (d, J=9.2 2H), 7.257.32 (m, 2H), 7.07- 7.09 (q, 1H), 6.99 (d, J=8.8 3H). 3.05 (s, 3H);
13C
NMR (DMSO d6) δ (ppm): 26.40, 109.09, 114.71, 121.14, 121.62,
122.84, 123.35, 127.44, 128.98, 135.60, 136.90, 148.30, 149.73,
151.40, 152.86, 165.16, 166.81;
MS (CI): m/z 397.5 [M+H]+.
Elemental analysis:
Found
Cal
C
60.69
60.60
H
N
O
4.32
14.14
12.23
4.29
14.14
12.12
3c). (i.e., 3, R1 = 2-Cl, R2 = 6-Me) Yield 3.56g (87%). Pure 3c (Acetone).
Purity (HPLC): 99.6%; M.F: C21H19ClN4O3; m.p: 184.6 ºC. HCl salt: 153.9
ºC;
PTs salt: not formed.
IR (KBr, cm-1): 3264, 3244, 1642, 1593, 1505, 1469, 1409, 1239.5,
1203.5, 928.5, 773, 667.2.
1H-NMR
(400MHz, DMSO d6) δ: 9.09 (s, 2H, exch with D2O), 8.79 (s, 1H),
8.02 (s, 1H, exch with D2O), 7.59(d, J=8.8 2H), 7.38 (d, J=2.4 1H) 7.35 (s,
1H), 7.13-7.26 (m, 5H), 2.78 (d, J=4.8 3H), 2.28 (s, 3H);
55
13C
NMR (DMSO d6) δ (ppm): 18.74, 26.22, 108.91, 114.15, 119.90,
120.00, 121.67, 127.05, 127.59, 129.32, 132.12, 134.02, 138.03,
138.85, 147.54, 150.60, 152.52, 153.09, 164.17, 166.28.
MS (CI): m/z 411.16 [M+H]+
Elemental analysis:
C
H
N
O
Found
61.48
4.65
13.71
12.0
Cal
61.46
4.63
13.65
11.7
3d). (i.e., 3, R1 = 4-Cl-3-CF3, R2 = 6-NO2) Yield 4.6g (91%). Pure 3d
(Acetone). Purity (HPLC): 99.6%; M.F: C21H15ClF3N5O5; m.p: 208.4 ºC.
HCl salt: 213.8 ºC; PTs salt: 216.2 ºC.
IR (KBr, cm-1): 3371, 3303, 3077, 1714, 1654, 1558, 1489, 1448, 1411,
1302, 1175, 1148, 1033, 922, 907, 836, 735, 714, 672, 610, 510, 459.
1H-NMR
(400MHz, DMSO d6) δ: 10.20(s, 1H), 9.79(s, 1H), 8.92(s, 1H),
8.79(d, J=4.8 1H), 8.51(d, J=5.6 1H), 8.41(s, 1H), 7.62(d, J=8.8 2H), 7.38
(d, J=2.8 1H), 7.15-7.22(dd, 3H), 2.78 (d, J=4.8 3H);
13C
NMR (DMSO d6) δ (ppm): 25.97, 108.77, 114.01, 120.65, 121.52,
121.81, 121.87, 122.10, 123.24, 128.06, 130.53, 130.84, 131.15,
131.46, 134.12, 136.52, 139.10, 148.31, 150.36, 151.62, 152.46,
163.76, 165.85.
MS (CI): m/z 510.6 [M+1]+
3e). (i.e., 3, R1 = 4-F, R2 = H) Yield 3.53g(93%). Pure 3e (Acetone). Purity
(HPLC): 93.4%; M.F: C20H17FN4O3; m.p: 221.5 ºC. HCl salt: 233.7 ºC; PTs
salt: 141.0 ºC
56
IR (KBr, cm-1): 3395, 3328, 3270, 1672, 1600, 1557, 1504, 1466, 1410,
1298, 1228, 1202, 931, 860, 835, 600, 556, and 511.
1H-NMR
(400MHz, DMSO d6) δ:
8.84 (s, 1H), 8.77 (bs, 2H), 8.50
(d,
J=5.6 1H), 7.57 (d, J=8.8 2H), 7.45-7.48 (q, 2H), 7.37 (d, J=2.8 1H), 7.137.17 (m, 5H), 2.78 (d, J=4.8 3H);
13C
NMR (DMSO d6) δ (ppm): 26.01, 108.70, 113.96, 115.18, 115.40,
120.02, 120.09, 121.45, 135.98, 137.59, 147.46, 150.31, 152.40,
152.70, 156.22, 158.58, 163.81, 166.06; MS (CI): m/z 381.5 [M+H]+.
Elemental analysis: C
H
N
O
Found
63.19
4.47
14.72
12.61
Cal
63.15
4.47
14.7
12.63
3f) (i.e., 3, R1 = 4-F, R2 = 2-NO2) Yield 4.1g(96%). Pure 3f (Acetone).
Purity (HPLC): 97.8%; M.F: C20H16FN5O5; m.p: 226.6 ºC. HCl salt: 209.3
ºC;
PTs salt: 215.5 ºC
IR (KBr, cm-1): 3330, 3092, 1709, 1660, 1557, 1500, 1453, 1409, 1340,
1296, 1186, 1133, 942, 922, 850.
1H-NMR
(400MHz,DMSO d6) δ: 9.96 (s, 1H), 9.53 (s, 1H), 8.80 (d, J=4.8
1H), 8.51(d, J=5.2 1H), 8.25-8.29 (q, 1H), 7.98-8.01(q, 1H), 7.60-7.70 (m,
3H), 7.38 (d, J=2.4 1H); 7.152-7.21 (m, 3H), 2.79 (s, 3H);
13C
NMR
(DMSO d6) δ (ppm): 26.19, 109.03, 111.96, 112.23, 114.25,
120.69, 121.76, 122.56, 122.78, 125.18, 125.26, 131.55, 137.19,
138.31, 138.39, 148.24, 150.68, 152.26, 152.52, 154.95, 157.37,
164.14, 164.21, 166.17.
57
MS (CI): m/z 426.2 [M+H]+
3g). (i.e., 3, R1 = 3-CF3, R2 = H) Yield3.51g (82%). Pure 3g (Acetone).
Purity (HPLC): 99.1%; M.F: C21H17F3N4O3; m.p: 187.6 ºC. HCl salt: 179.9
ºC;
PTs salt: 212.5 ºC.
IR (KBr, cm-1): 3358, 3090, 1708, 1654, 1568, 1541, 1505, 1465, 1407,
1338, 1300, 1228, 1195, 1170, 1126, 1096, 1072, 993, 926, 879, 846,
786, 702, 661, 564, 510, 487.
1H-NMR
(400MHz,CDCl3) δ: 8.46 (d, J=5.2 1H), 8.36 (d, J=5.2 1H),
8.33(s, 1H), 8.11(s, 1H), 7.70 (s, 1H) 7.65 (d, J=8 1H), 7.56 (d, J=2.4 1H),
7.36 (d, J=8.8 3H), 7.24 (s, 1H), 7.15-7.17 (q, 1H), 6.98 (d, J=8.8 2H),
3.05 (s, 3H);
13C
NMR (DMSO d6) δ (ppm): 25.66, 109.41, 113.42, 114.64, 118.13,
120.18, 120.90, 121.11, 122.31, 125.01, 128.87, 130.36, 130.68,
136.55, 139.76, 148.00, 149.27, 152.52, 164.16, 166.11.
MS (CI): m/z 431.6 [M+H]+.
Elemental analysis:
C
H
N
O
Found
58.63
4.00
13.15
11.21
Cal
58.60
3.95
13.02
11.16
3h). (i.e., 39, R1 = 2-Me, R2 = 3-Me) Yield 3.78(97%). Pure 3h (Acetone).
Purity (HPLC): 99.3%; M.F: C22H22N4O3; m.p: 194.1 ºC. HCl salt: 162.9
ºC;
PTs salt: 185.6 ºC.
IR (KBr, cm-1): 3412, 3284, 1681, 1643, 1604, 1567, 1534, 1506, 1466,
1406, 1295, 1230, 1200, 1099, 925, 856, 686, 593, 546, 509.
58
1H-NMR
(400MHz,DMSO d6) δ: 9.11(s, 1H, exch with D2O), 8.76-8.79 (q,
1H), 8.50 (d, J=5.6 1H), 8.01(s, 1H), 7.52-7.60(dd, 3H), 7.39 (d, J=2.4
1H), 7.13-7.16 (m, 3H), 7.02-7.06 (t, 1H), 6.91(d, J=7.6 1H), 2.79 (d,
J=4.8 3H), 2.26 (s, 3H), 2.15(s, 3H);
13C
NMR (DMSO d6) δ (ppm): 13.64, 20.33, 26.01, 108.72, 113.93,
119.64, 120.55, 121.45, 125.02, 125.24, 127.67, 136.59, 136.90,
137.97, 147.19, 150.21, 152.29, 152.98, 163.72, 166.17.
MS (CI): m/z 391.6 [M+H]+.
3i). (i.e., 39, R1= 2-Me, R2 = 4-Me) Yield 3.82g (98%). Pure 3i
(Acetone).
Purity (HPLC): 94.3%; M.F: C22H22N4O3; m.p: 181.5 ºC. HCl salt: 216.2
ºC;
PTs salt: 177.6 ºC.
IR (KBr, cm-1): 3288, 1686, 1646, 1601, 1557, 1505, 1467, 1297, 1197,
928, 829, 784, 691, 545, 510.
1H-NMR
(400MHz,DMSO d6) δ:
9.13 (s, 1H), 8.77-8.8 (q, 1H), 8.50(d,
J=5.6 1H), 7.91 (s, 1H), 7.57-7.65 (dd, 3H), 7.39 (d, J=2.8 1H), 7.15 (d,
J=8.8 3H), 6.70 (s, 1H), 6.95-6.97 (d, J=8.4 1H), 2.79 (d, J=4.8 3H), 2.23
(s, 3H), 2.21(s, 3H).
13C
NMR
(DMSO d6) δ (ppm): 17.84, 20.33, 26.02, 108.81, 113.95,
119.63, 121.44, 121.67, 126.59, 128.07, 130.73, 131.81, 134.67,
137.96, 147.19, 150.13, 152.17, 152.86, 163.65, 166.25;
MS (CI): m/z 391 [M+H]+.
59
3j). (i.e., 39, R1 = 2-Me, R2 = 5-Me) Yield 3.66g (94%). Pure 3j (Acetone).
Purity (HPLC): 98.7; M.F: C22H22N4O3; m.p: 186.4 ºC. HCl salt: 154.9 ºC;
PTs salt: 193.8 ºC.
IR (KBr, cm-1): 3298, 1640, 1555, 1537, 1505, 1406, 1288, 1227, 1196,
996, 922, 833, 799, 668, 563.
1H-NMR
(400MHz, DMSO d6) δ: 9.16 (s, 1H, exch with D2O), 8.78 (d,
J=4.8 1H), 8.51(d, J=5.6 1H), 7.90 (s, 1H), 7.67 (s, 1H), 7.59 (d, J=9.2
2H), 7.38 (d, J=2.8 1H), 7.16(d, J= 8.8 3H), 7.05(d, J=2 1H), 6.78(d,
J=7.2 1H), 2.79 (d, J=4.8 3H), 2.23 (d, J=20.8 6H);
13C
NMR (DMSO d6) δ (ppm): 17.44, 20.89, 25.98, 30.61, 108.73, 113.93,
119.71, 121.42, 121.86, 123.48, 124.61, 129.98, 135.10, 137.09,
137.82, 147.36, 150.30, 152.45, 152.72, 163.84, 166.06;
MS (CI): m/z 391 [M+H]+.
3k). (i.e., 3, R1 = 2-Me, R2 = 6-Me) Yield 3.74g (96%). Pure 3k (Acetone).
Purity (HPLC): 99.5%; M.F: C22H22N4O3; m.p: 220.7 ºC. HCl salt: 197.5 ºC;
PTs salt: not formed.
IR (KBr, cm-1): 3310, 2918,1673, 1641, 1590,1557, 1503, 1468, 1405,
1295, 1259, 1227,1199,1147.9, 921.8, 831, 768, 701.7, 563.5, 482
1H-NMR
(400MHz,DMSO d6) δ: 8.93 (s, 1H), 8.79 (d, J=8.8 1H), 8.49 (d,
J=5.6 1H), 7.77 (s, 1H), 7.58 (d, J=9.2 2H), 7.37 (d, J=2.4 1H), 7.12-7.14
(m, 3H), 7.07 (s, 3H), 2.78 (d, J=4.8 3H), 2.22 (s, 6H);
60
13C
NMR
(DMSO d6) δ (ppm): 18.43, 26.21, 108.87, 114.14, 119.88,
121.62, 126.32, 127.97, 135.35, 135.86, 138.37, 147.31, 150.59,
152.51, 153.47, 164.18, 166.32;
MS (CI): m/z 391 [M+H]+.
3l). (i.e., 3, R1= 3-Me, R2 = 4-Me) Yield 3.7g (95%). Pure 3l (Acetone).
Purity (HPLC): 95.6%; M.F: C22H22N4O3; m.p: 190.9 ºC. HCl salt: 199.6 ºC;
PTs salt: not formed.
IR (KBr, cm-1): 3317.2, 1673.5, 1642.3, 1591.2, 1556.7, 1503.6, 1405.5,
1295.4, 1227.3, 1199.5, 921.7, 768.
1H-NMR
(400MHz,DMSO d6) δ: 8.81 (bs, 2H), 8.55 (s, 1H), 8.51 (d,
J=16.8 1H), 7.58 (d, J=7.5 2H), 7.38 (d, J=2.4 1H), 7.24 (bs, 1H), 7.147.20 (m, 4H), 7.03 (d, J=8 1H) 2.79 (d, J=4.8 3H), 2.17 (d, J=14.8 6H);
13C
NMR (DMSO) δ (ppm): 18.96, 19.92, 26.22, 109.07, 114.29, 116.24,
120.01, 120.25, 121.76, 130.02, 130.12, 136.79, 137.35, 147.70,
150.69, 152.49, 152.89, 164.26, 166.41;
MS (CI): m/z 391 [M+H]+.
3m). (i.e., 3, R1 = 3-Me, R2 = 5-Me) Yield 3.74g (96%). Pure 3m (Acetone).
Purity (HPLC): 98.3%; M.F: C22H22N4O3; m.p: 212.1 ºC. HCl salt: 178.4 ºC;
PTs salt: 220.9 ºC
IR (KBr, cm-1): 3300, 1651, 1551, 1504, 1467, 1296, 1234, 1205, 922,
834, 686, 562.
61
1H-NMR
(400MHz, DMSO d6) δ: 8.78 (s, 2H), 8.55 (s, 1H), 8.5 (d, J=5.6
1H) 7.57 (d, J=8.8 2H), 7.38 (d, J=2.4 1H), 7.08-7.16 (m, 5H), 6.62 (s,
1H), 2.78 (d, J=4.8 3H), 2.23 (s, 6H);
13C
NMR (DMSO) δ (ppm): 21.13, 26.00, 108.66, 113.96, 116.01, 119.85,
121.44, 123.53, 137.66, 137.73, 139.45, 147.35, 150.33, 152.41,
152.52, 163.78, 166.06;
MS (CI): m/z 391 [M+H]+.
3n). (i.e., 3, R1 = 3-NO2, R2 = H) Yield 3.5g (86%). Pure 3n (Acetone).
Purity (HPLC): 92.5%;
M.F: C20H17N5O5; m.p: 199.6 ºC. HCl salt: 194.7 ºC; PTs salt: 218.3 ºC
IR (KBr, cm-1): 3361, 1720, 1654, 1600, 1560, 1504, 1405, 1347, 1299,
1233, 1193, 1163, 931, 880, 833, 735, 672, 567, 511, 483.
1H-NMR
(400MHz,DMSO d6) δ: 9.41 (s, 1H, exch with D2O), 9.13 (s, 1H,
exch with D2O), 8.83 (d, J=4.4 1H), 8.58 (s, 1H), 8.52 (d, J=5.6 1H), 7.84
(d, J=8.4 1H), 7.74 (d, J=8 1H), 7.58-7.63 (t, 3H), 7.41(s, 1H), 7.19(d,
J=9.2 3H), 2.79 (d, J= 4.4 3H);
13C
NMR (DMSO d6) δ (ppm): 26.24, 109.29, 112.43, 114.36, 116.73,
120.74, 121.74, 124.58, 130.36, 137.26, 141.08, 148.10, 148.40,
150.37, 152.04, 152.69, 163.93, 166.61;
MS (CI): m/z 408 [M+H]+.
3o). (i.e., 3, R1 = 4-NO2, R2 = H) Yield 3.7g(91%). Pure 3o (Acetone).
Purity (HPLC): 97%;
M.F: C20H17N5O5; m.p: 242.2 ºC. HCl salt: 248.3 ºC; PTs salt: 233.5 ºC
62
IR (KBr, cm-1): 3391.8, 3335.0, 3247.6, 1682, 1654, 1552.9, 1531.5,
1495.1, 1415.1, 1335.2, 1197.8, 1115.1, 857.3, 753.3.
1H-NMR
(400MHz, DMSO d6) δ: 9.51 (s, 1H, exch with D2O), 9.09 (s, 1H,
exch with D2O), 8.78(d, J=4.4 1H), 8.51(d, J=5.6 1H), 8.21(d, J=9.2 2H),
7.71 (d, J =9.2 2H), 7.61 (d, J= 8.8 2H), 7.39 (d, J=2.4 1H), 7.15-7.21 (m,
3H), 2.79 (d, J=4.8 3H);
13C
NMR (DMSO d6) δ (ppm): 26.04, 108.68, 114.05, 117.53, 120.50,
121.57, 125.19, 136.91, 141.04, 146.37, 147.96, 150.39, 152.05,
152.44, 163.81, 165.97.
MS (CI): m/z 408 [M+H]+.
Elemental analysis:
C
H
N
O
Found
67.70
5.61
14.32
12.31
Cal
67.69
5.64
14.35
12.30