Molecules bearing associa'tive groups
The present invention relates to . nitrogenous
associative molecules comprising at least one unit
5 rendering them capable of associating with one another or
with a filler, via noncovalent bonds, and comprising a
function capable of reacting with a polymer containing
'^ unsaturations so as to form a covalent bond with said
polymer. ♦
10 In the industrial field, mixtures -©:€ polymers with
fillers are often used. In order for such mixtures to have good properties, means for improving the dispersion of the fillers within the polymers are constantly being sought. One of the means for achieving this result is the 15 use of coupling agents capable of establishing interactions between the polymer and the filler.
Agents for coupling a polymer with a filler comprising nitrogenous dipoles are described in the documents published under numbers US 7 186 845 B2 and 20 JP20082081'63.
These documents describe the modification of
polymers com^irising diene units with nitrogenous dipolar
compounds comprising, in addition, a heterocycle, said
heterocycle itself comprising a nitrogen atom, and an
25 oxygen and/or sulfur atom.
,y. More particularly, the compounds described are ^ nitrones bearing oxazoline or thiazoline functions, for instance (-(2-oxazolyl)phenyl-N-methylnitrone).

CH.
CVQ

H N

i

When diene polymers are made to react with such compounds,'' the polymers resultii^g therefrom will bear the oxazoline or thiazoline rings.
These rings present on the polymer are capable of
5 reacting, in turn, with surface functions of the fillers
(such as carbon black or silica) with which the polymers
are mixed. This reaction results in the forming of
"^ covalent bonds between the polymer modified with the coupling agent and the filler owing to the opening of the
10 oxazoline or thiazoline ring. Indeed, as-:-it is described in document US 7 186 845 B2, the oxazoline and/or thiazoline rings are capable of opening in the presence of a nucleophile which may, for example, be present at the surface of the filler.
15 The forming of such covalent bonds has, on the other
hand, drawbacks during the preparation of mixtures comprising these polymers, modified with coupling agents,
with fillers. In particular, the existence of these
I
covalent bonds formed early on, between the polymer and
20 the fillers, makes these mixtures very viscous in the non-crosslinked state, which makes all operations prior to ' the crcifslinking (vulcanization) of rubber-based formulations difficult, in particular the preparation of mixtures of constituents, and the forming thereof; these
25 drawbacks have a strong impact on industrial
pro-ductivity. It is therefore desirable to propose novel
, '• molecules which do not have the above drawbacks, i.e.
molecules which are capable, after reaction with a
polymer and mixing with a filler, of not forming covalent
30 bonds with the filler and therefore of knot causing too great an increase in the viscosity of the' mixture.
A- subject of the invention is a compound comprising at least one group Q and at least one group A linked

together by at least and preferably one "spacer" group
Sp, in whi'ch: ^
Q comprises a dipole containing at least and
preferably one nitrogen atom,
5 - A comprises an associative group comprising at
least one nitrogen atom,
- Sp is an atom or a group of atoms forming a link
^ between Q and A.
A polymer grafted with a compound as defined above 10 is mixed with fillers, as said compound-e-stablishes only labile bonds with the fillers, which makes it possible to provide good polymer-filler interaction, beneficial for the final properties of the polymer, but without the drawbacks that too strong a polymer-filler interaction 15 could cause.
The compounds which are subjects of the invention provide good interaction with the fillers by establishing labile bonds between the polymer chains and the filler, 20 and thus Idmit the processing problems.
The terjji "dipole" is intended to mean a function capable of forming a 1,3 dipolar addition on an unsaturated carbon-carbon bond. 25
.-:■. The term "associative group" is intended to mean
, • groups capable of associating with one another via
hydrogen, ionic and/or hydrophobic bonds. They are,
according to one preferred embodiment of the invention,
30 groups capable of associating via hydrog^ bonds.
When the associative groups are capable of associating via hydrogen bonds, each associative group comprises at least one donor "site" and one acceptor site

with respect to the hydrogen bond such that two identical
associative' groups- are self--^complementary and can
associate with one another by forming at least two
hydrogen bonds. ' ,
5 The associative groups according to the invention
are also capable of associating via hydrogen, ionic and/or hydrophobic bonds with functions present on the fillers.
10 The compounds according to the inve-a^feion comprising
a group Q, a "spacer" group and an associative group can, for example, be represented by formula (la) below:
A-Sp-Q (la). The compounds according to the invention comprising 15 a group Q, a "spacer" group and two associative groups */ can, for example, be represented by formula (lb) below:
A
I
Similarly, the compounds according to the invention comprising two groups Q, a "spacer" group and an 20 associative ^roup can, for example, be represented by formula (Ic) below:
Q
. ■ I ■ ■■
O A
According to the same principle, the compounds
according to the invention comprising two groups Q, a
25 "spacer" group and two associative groups can, for
T
example, be represented by formula (Id) i^elow:
Q
I Q-Sp-A
I
A . (Id).

Preferably, the associative group is chosen from an imidazolidinyl, ureyl, bis-urevl, ureidopyrimidyl and triazolyl group.
Preferably, the group, A corresponds to one of the formulae (II) to (VI) below:
T - •■
X
* (II) o
I I
H H
(III)
o o

1

10

II II
H H H H

(IV)

N^ O
o^u^ir^H-^
I I
H H
V)

//

15

(VI)

20

i
wherein:
R denotes a hydrocarbon-based ^oup which can optionally contain heteroatoms,
- X denotes an oxygen or sulfur atom, preferably an oxygen atom.

Preferably, the group A comprises a dinitrogenous or
trinitrogehous heterocycle, containing 5 or 6 atoms,
which is preferably dinitrogenous, and which comprises at
least one carbonyl function,
5 Even more preferably, the group A comprises an
imidazolidinyl group of the formula (II).
The group Q is capable of bonding to a polymer chain
'' comprising at least one unsaturation by covalent bonding
(grafting) . Preferably, tlie group Q comprises a nitrile
10 oxide, nitrone or nitrile imine functioR---which can bond
to a polymer bearing unsaturations, via a cycloaddition
of [3+2] type.
Preferably, the group Q is a group of formula (VII), , 15 (VIII) or (IX) below
1
Ri O
X
R2 R3
(VII) «
R4—C=N-»^0
20 ' (VIII)
R5—C=N-»-N-Re
(IX)
in ,which Rl to R6 are chosen independently from a spacer
25 ', group Sp, a hydrogen atom, a linear or branched C1-C20
alkyl group, a linear or branched C3-C20 cycloalkyl group,
a linear or branched C6-C20 aryl group, and a group of
formula (X) i


30

(X)

'4

in which n represents 1, 2, 3, 4 or 5 and each Y independently represents a spa^cer group Sp, an alkyl group or a halogen.
5 The "spacer" group Sp makes it possible to link at
least one group Q and/or at least one associative group A, and thus may be of any type known per se. However, the
** "spacer" group must interfere little or not at all with the groups Q and associative groups of the compound
10 according to the invention. —■•'
Said "spacer" group is therefore considered to be a group that is inert with respect to the group Q and the associative group. The expression ""spacer" which is inert with respect to the group Q" is intended to mean:
15 which does not have alkenyl or alkynyl functions capable
of reacting with this group. The expression ""spacer"
which is inert with respect to the associative group" is
intended to mean: which does not comprise associative
I functions as defined according to the invention.
20 The "Spacer" group is preferably a linear, branched
or cyclic hydrocarbon-based chain, and can contain one or
more aromati^ radicals, and/or one or more heteroatoms.
Said chain can optionally be substituted, provided that
the substituents are inert with respect to the groups Q
25 and associative groups.
0- According to one preferred embodiment, the "spacer"
.. ■ group is a linear or branched C1-C24, preferably Ci-Cio,,
alkyl chain optionally interrupted with one or more
nitrogen or oxygen atoms, more preferentially a linear
30 Ci-Ce alkyl chain. k
Preferably, the group Q is a group of formula (XI):

CNO
>-Rfl
(XI) in which R7 and R8 independently represent a C1-C5 alkyl group or a halogen, and preferably R7 and R8 independently represent a methyl group or a chlorine atom, and the group A is a group of formula (XII):

10

.N NH
Y
o
(XII).

Preferably, the compound which is the subject of the
invention is chosen from the compounds of formulae (XIII)
to (XXI) below: I
o-

15
(XIII)

(XV)
o-
I

(XVI)
o
V-NH

/ o-
(XVII)
1>



0 Nt

(XVIII)

10

(XIX)

0 (XX)

^-x^

(XXI)

10

I
According to another embodiment of the invention, the compound intended for grafting the polymer in accordanqe with the invention is chosen from the compound of formulae (XXft) to (XXIII) below:

^-N^^^F


11

(XXIII)
♦
in which R is chosen from a spacer group Sp, a hydrogen atom, a linear or branched C1-C20 alkyl group, a linear or branched C3-C20 cycloalkyl group, a linear or branched Ce-C20 aryl group, and a group of formula (X)

10 (X)
in which n represents 1, 2, 3, 4 or 5 and each Y
independently represents a spacer group Sp, an alkyl
group or a halide.
I ■ 15 The invention is also illustrated by the following
nonlimiting «xamples.
EXEMPLARY EMBODIMENTS ..
The structural analysis and also the determination of the
20 mo3?ar purities of the synthetic molecules are carried out
■. ' by NMR analysis. The spectra are acquired on a Bruker
' Avance 500 MHz spectrometer equipped with a BBIz-grad
5 mm "broad-band" probe. The quantitative ■"'H NMR
experiment uses a simple 30° pulse jsequence and a
25 repetition delay of 3 seconds between each of the 64
acquis'itions. The samples are solubilized in deuterated
dimethyl sulfoxide (DMSO). This solvent is also used for

the lock signal. The calibration is carried out on the proton signal for. the deuterated DMSO at 2.44 ppm relative to a TMS reference at 0 ppm. The ■''H NMR spectrum coupled with the 2D HSQC 1H/13C and HMBC 'IH/ISC 5 experiments enable the structural determination of the molecules (cf. assignment tables) . The molar quantifications are carried out on the basis of the > quantitative ID ■''H NMR spectrum.
The infrared measurement makes it possible to validate
10 the presence of the nitrile oxide group borne by an
aromatic. The spectra are acquired on a Vertex 70
Fourier transform spectrometer fitted with a DTGS
detector. The spectra are acquired in 32 scans between
4000 cm"-"- and 400 cm"-^ with a resolution of 2 cm""^. The
. 15 samples are prepared in the form of KBr pellets. The
'/ nitrile oxide function borne by the aromatic is
characterized by a band at 22 95 cm"""".
The mass spectrometry analysis is carried out by direct
injection in electrospray ionization mode (DI/ESI). The
20 analyses w'ere carried out on a Bruker HCT spectrometer
(flow rate 600 jiL/min, nebulizing gas pressure 10 psi, ^ nebulizing ga"% flow rate 4 L/min) .
Example 1: Preparation of 1-(2-(3^-nitriloxymesityl-1'- .
25 oxy)ethyl)imidazolidin-2-one
■?■ 0-
I

^^0'
[ NH
This compound ,can be prepared from hydroxyethyl-imidazolidone mesitol according to the following 30 synthesis scheme.

13

HO^

O
A:
NH

SOCI2 CH2CI2

1 NH '

T1CI4 MeOCHCl2 CIHjClj *"

Oo^ ^H

NHjGH EtOH



NaOCI
CH2a2

a) Preparation of 3-hydroxy-2,4,6-trimethylbenzaldehyde

10
15

This q^mpound can be obtained according to a' procedure described in the following article: Yakubov, A. P.; Tsyganov, D. V.; Belen'kii, L. I.; Krayushkin, M. M.; Bulletin of the Academy of Sciences of the USSR, Division of- Chemical Science (English Translation); vol. 40; nb. 7.2; (1991); p. 1427 - 1432; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 7; (1991); p. 1609 -1615.
b) Preparation of 1-(2-chloroethyl)imidaZolidin-2-one:

14
This product is described in tlie article Nagarajan K. ,
Arya V. Pi , 'Shah R. K.; Indian Journal of Chemistry,
Section B: Organic Chemistry Including Medicinal
5 Chemistry; 21; 10; 1982; 928-940.
Thionyl chloride (34 ml, 0.47 mol) is added, dropwise, at >
ambient temperature, over a period of 35 minutes, to a solution of 1-(2-hydroxyethyl)imidazolidin-2-one (50.0 g,
10 0.39 mol) in dichloromethane (250 ml) . At' the end of the addition, the temperature of the reaction medium is 35°C. The reaction medium is maintained at a temperature of 35-40°C for 2.5 hours. After evaporation under reduced pressure (Tbath 35°C, 15-17 mbar) , the crude product is
15 obtained (67 g). This crude is crystallized from a mixture of acetone and petroleum ether (35 g for 950 ml of acetone and 820 ml of petroleum ether at -24°C for 10 to 15 hours). The crystals are filtered off, -washed with petroleum ether (twice with 40 ml), then dried for 10 to
20 15 hours under atmospheric pressure at ambient temperature.
A white soli's (33.3 g, yield 66%) with a melting point of 93°C is obtained. The molar purity is greater than 97% (^H NMR) . ■

25

A ■ ■'"H and "'■^C NMR characterization is provided in the following table 1.
O
II

\_/

^5'

15
Table 1

'Atom 5 ^H (ppm) + mult. 5 ^^C (ppm)
1 - 162.1
2 3.17 (t) 37.5
3 3.33 (t) 44.7
4 3.29 (t] 45.0
5 3.62 (t) 42.4
Solvent used: DMSO - Calibration on the signal of the DMSO at 2.44 ppm in ^H, 39.5 ppm in "c.

c)

Preparation

of

2,4,6-trimethyl-3-(2-(2-

oxoimidazolidin-1-yl)ethoxy)benzaldehyde:
0^\ M
10
15
20

3-Hydroxy-2,4,6-trimethylbenzaldehyde (11.90 g,
0.0'73 mol) ^n anhydrous toluene (300 ml) is added dropwise to a solution of sodium (1.63 g, 0.071 mol) in , methanol (60 ml) . The mixture is brought to reflux and then the methanol is distilled off (volume of azeotropic mixture collected 80-90 ml). After a return to 80-90°C, (2-chloroethyl)imidazolidin-2-one (10.45 g, 0.070 mol) is added in one step to the reaction medium. After refluxing for 7 hours, the solvents are evaporated off under reduced pressure (Tbath 50°C, 25 mbar).i Dichloromethane (150 ml) and water (30 ml) are added ''to the mixture obtained. The organic phase is then washed twice with water (20 ml) . After drying over Na2S04, the dichloromethane is evaporated off under reduced pressure

16

10
15

(Tbath 35°C, 33 mbar) . Petroleum ether {3 times 50 ml) and water (50 ml) are added to the mixture obtained (24 g) and the prfecipitate obtained is filtered off and washed on the filter with water ' (15 ml) and petroleum ether (twice with 15 ml).
The product obtained is repurified by washing the prpduct in solution in dichloromethane (80 ml) with a solution of NaOH at 4% in water (3 times with 60 ml) . After evaporation of the solvents under reduced pressure, the product is precipitated from petroleum ether. The precipitate is filtered off and dried for 15 to 20 hours under atmospheric pressure at ambient temperature. A white solid (8.55 g, yield 44%) with a melting point of 139°C is obtained. The molar purity is greater than 94% (-"-H NMR) .

A ■''H and ■'■■'c NMR characterization is provided in the
following table 2.

16
I
,15
o
1 ^5^ O ^15 U / ^N^ ^6/ ^7^ ^13^ ^(
9^ ^10 ^12

20

Table 2

Atom 5 ^H (ppm) + mult. . 5 •^''C (ppm)
1 - 163.1
2 ~ 4.74 (s) -
3 3.40 (t) ''■^ 4 3.65 (t) 46.8
5 3.52 (t) 43.9
6 3.79 (t) 71.3

17

7 - 153.9
8 - »*
■ 9 - '2.23/2.46 (s) 16.5/19.8
10 6.84 131.7
11 - ■*•
12 2.23/2.46 (s) 16.5/19.8
13 - *
14 ~ 10.46,(s) 193.0
15 - •*■
16 2.46 (s) 12.1
* 131.4/133.5/136.6/136.7 ppm: The aromatic ring -^^C chemical shifts are not assigned.
Solvent used: CDCI3 - Calibration on the signal of chloroform at 7.2 ppm in """H, 77 ppm in "'■^C.

d)

Preparation

of

2,4,6-trimeth^l-3-(2- (2-

oxoimidazolidin-1-yl)ethoxy)benzaldehyde oxime:
10

15
20

A solution of aqueous hydroxylamine (2.83 g, 0.043 mol,
50% in water) in ethanol (10 ml) is added to a solution
of 2,4,6-trimethyl-3-(2-(2-oxoimidazolidin-l-
yl)ethoxy)benzaldehyde (7.90 g, 0.029 mol) in ethanol
(70 ml) maintained at a temperature of 45°C. The reaction medium is then stirred for 2.5 hours 4t a temperature between 50 and 55°C. The solvent is evaporated off under reduced pressure (Tbath 37°C, 35 mbar) . Petroleum ether
(80 ml) is added to the crude obtained. The precipitate

18
obtained is filtered off, washed with petroleum ether
(twice with 20 ml) and dried for 15 to 20 hours under
atmospheric pressure at ambient temperature.
A white solid (7.82 g, yield 94%) with a melting point of
165°C is obtained.
The molar purity is greater than 84% (the remaining 16%
comprise in particular 7 mol% of EtOH) according to the
^H NMR.

13
10

A

H and C NMR characterization is provided in the

following table 3.
o Y
V /^\ ^O^ ^^K ^^t^ /OH
HN j I II
9-^ ^10 ^12

15

Table 3

Atom 5 -^H (ppm) + mult. 5 ^-^C (ppm)
1* - 162.0
2 ~ 6.30 (s) -
3 3.19 (t) 37.1
4 3.44 (t) 45.5
5 3.34 (t) 43.2
6 3.69 (t) 70.3
7 - 153.5
8 -
9 2.14 (s) 15-4 10 - 130.5
11 - ■*•
12 2.18 (s) 19.9

19

13 - *
14 ~'8.20 (s) '147.4
15 ■~ 11.10 (s) -
16 - *
17 2.17 (s) 12.9
13^
* 129.3/129.5/131.9 ppm: The aromatic ring "'■'C chemical shifts are not assigned, three signals are detected (probably two carbons under one and the same signal).
Solvent used: DMSO - Calibration on the signal of DMSO at 2.44 ppm in ^H, 39.5 ppm in ^^C.

e)

Preparation

of

2,4,6-trimethyl-3-(2-(2-oxo-

1

10

imidazolidin-1-yl)ethoxy)nitrile
according to the invention;

oxide,

compound

0-

15
20
25

An 1 aqueous solution of NaOCl (4% of active chlorine, ^ 52 ml) is added, dropwise, over a period of 5-7 minutes, to a solution of oxime previously prepared (6.00 g, 0.021 mol) in dichloromethane (250 ml), at a temperature of^ 2°C. The temperature of the reaction medium is maintained between 0 and -4°C. The reaction medium is then stirred for 3 hours at a temperature between 0 and 5°C. The organic phase is then separated. The aqueous phase is extracted with dichloromethane (twice with 15 ml). The organic phases are combined!and then washed with water (twice with 20 ml, and dried with Na2S04. The solvent volume is reduced by evaporation under reduced pressure (Tbath 22°C, 220 mbar) to 50-60 ml. Petroleum

20
ether (75. ml) is then added and the solution is placed at -18°C for 10-15 hours. The ^precipitate obtained is filtered o,ff-and • washed with an ethyl acetate/petroleum ether (1/2) mixture (10 ml)- and, finally, dried for 10-15 hours under atmospheric pressure at ambient temperature. A white solid (4.70 g, yield 79%) with a melting point of 156°C is obtained. The molar purity is greater than 85% (-^H NMR) .

10

H and C NMR characterization is '"ptovided in the

following table 4.

O
\HN I
2\ i
3 ^

■"--.^'-^ykn'^"
'12
J 5^
16
M4
~13

•i

Table 4

15

Atom 5 -^H (ppm) + mult. 1 n
5 ^"C (ppm)
1 - Not detected, not assigned
2 - 4.59 (s) -
3 3.41 (t) 38.3
4 3.64 (t) 47.0
5 3.51 (t) 44.1
6 3.79 (t) 71.5
7 - 153.6
8 - 134.4/137.3*
9 2.32 (s) ''■' 10 - 112.8
11 ^ Not detected, not assigned

21

12 - 134.4/137.3*
13 2.31 (s) ^20.2
^14 '6.85 (s) 130.3
15 - 134.4/137.3*
16 2.20 (s) 16.4
*The aromatic carbons 8, 12 and 15 are not assigned. Two, signals are observed in "'■■^C NMR, there are probably two carbons which leave under the same signal.
The -C=N->0 function exhibits a characteristic IR band at

-1
22 95 cm'

1

Solvent used: CDCI3 - Calibration on the signal of 10 chloroform at 7.2 ppm in ■''H, 77 ppm in ''"^C.
Example 2: Preparation of 2-[2-(2-oxoimidazolidin-l-
yl)ethoxylbenzonitrile oxide I


15

20

Th'is compound can be prepared from salicylic aldehyde and 2-chloroethylimida2olidone according to the following synthesis scheme:

22

a) The preparation of 1-(2-Ghloroethyl)imidazolidin-2-one is described in example 1.

10

b) Preparation of 2-[2-(2-oxoimidazolidin-l- . yl)ethoxy]benzaldehyde


K2CO3 (87.1 g, 0.631 mol) is added to a solution of > 15.■ salicylic aldehyde (22.0 g, 0.180 mol) in DMF (100 ml).
The mixture is stirred at 52°C. After 10 minutes at this
temperature, 1-(2-chloroethyl)imidazolidin-2-one
(40.0 g, 0.270 mol, purity > 90%) is adjded portionwise.
The temperature of 'the mixture is brought to 90°C (Tbath)
20 over the course of one hour and this temperature is
maintained for 5 hours. After return to ambient
temperature, the mixture is diluted with water (1.3 1)

23

10
15

and the product is extracted with CH2CI2 (500 ml, 5 times
I',
100 ml) . The organic phases aie combined, then washed with water (twice with 50 ml) and evaporated until a reaction crude of 70-80 g Is obtained (dense suspension) (Tbath = 40°C) . The reaction crude is taken up in Et20 (120 ml) and the suspension is stirred at ambient temperature for 2 0 minutes. The precipitate obtained is filtered off and washed with a mixture of DMF/Et20/H2P (5 ml/20 ml/15 ml) then with Et20 (twice with 10 ml). The solid obtained is dried at ambient temperature.
A solid (30.6 g, yield 73%) with a melting point of 150°C is obtained. The molar purity is greater than 84% (^H NMR) .
The 2-[2-(2-oxoimidazolidin-l-yl)ethoxy]benzaldehyde
obtained is directly used in the next step without
further purification.

"^H and ^^C NMR characterization

HN

J.
/ ^N'^ ^S'^ ^6-^ ^10
J II I

20

Table 5

Atom 5 ^H (ppm) 5 ^''C (ppm)
1 - 164.9
2 3.15 37.3
3 3.39 "1
4 3.44 42.r
5 4.16 66.5
6 - 160.5

24

7 7.17 113.2
8 7.59 '' 136.2
V -9 7.02 120.5
10 7.63 ' 127.3
11 - 124.0
12 10.31 189.1
Solvent used: DMSO - Calibration on the signal of DMSO at 2.44 ppm in ^H, 39.5 ppm in ^^C.
c) Preparation of 2-[2-(2-oxoimidazolidin-l-yl)ethoxy]benzaldehyde oxime

A solution of 2-[2-(2-oxoimidazolidin-l-yl)ethoxy]benz-
10 aldehyde i.10.0 g, 0.043 mol) in EtOH (100 ml) is brought
to 50°C. At this temperature, a solution of
hydroxylamine (4.5 g, 0.068 mol, 50% in water, Aldrich) '
in EtOH (10 ml) is added. The reaction medium- is then ,
stirred for 6 hours at a temperature between 50 °C and
15 7 0°C. The reaction medium is evaporated under reduced
pressure (Tbath 45°C, 65-70 mbar) until a suspension is
\ obtained. The reaction crude is then taken up in water
(5 ml) . The solution obtained is cooled to 5°C and
maintained at this temperature for 15 hours. The
20 precipitate obtained is filtered off and washed on the
filter with an EtOH/water (2 ml/2 ml) mixture, then with
an Et-OH/petroleum ether (1 ml/4 ml) mixture, then with
petroleum ether (2x10 ml) . The solid is then dried under
atmospheric pressure at ambient temperature.

25
A white solid (9.25 g, yield 87%) with a melting point
of 88°C is obtained. ''
The molar purity is greater than 99% (-"-H NMR) .
■"^H and ''^'^C NMR characterization

,f
i •^~'-
HN'-^ OH
3'' S—O 12=1/

10

Table 6

Atom 5 -^H (ppm) 5 ^"^C (ppm)
1 - 162.0
2 3.17 37.4
3 3.37 45.4
4 3.39 42.6
5 4.03 66.6
6 - 155.8
>»7 7.01 113.0
8 7.28 130.7
9 6.89 121.2
10 7.61 125.2
11 - 120.9
12 . 8.25 143.3
Solvent used: DMSO = Calibration on the signal of DMSO at
2.44 ppm in ^H, 39.5 ppm in ^^C. ji

26
d) Preparation of 2-[2-(2-oxoimidazolidin-l-yl) ethoxy]benzonit:rile oxide *

5 An aqueous solution of NaOCl in water (157 ml, Aldrich, > 4% of active chlorine) is added dt"5pwise, over a period of 10 minutes, to a suspension of 2-[2-(2-oxo-imidazolidin-1-yl)ethoxyjbenzaldehyde oxime (20.2 g, 0.081 mol) in CH2CI2 (400 ml) at -1°C. The reaction
10 medium is then stirred for 2 0 minutes. The aqueous and
; organic phases are separated and the aqueous phase is
"^ extracted with CH2CI2 (twice at 75 ml) . The combined
organic phases are washed with water (3 times 10 ml) and
dried over Na2S04. The phases are concentrated to 100 ml
15 under reduced pressure at ambient pressure. 50 ml of petroleum' ether are added. The solution is cooled to -18°C (3 hours). The precipitate is filtered off, washed with CH2Cl2/petroleiam ether (5 ml/10 ml; then 5 ml/20 ml; then 0 ml/20 ml), then dried under atmospheric pressure
20 at ambient temperature.
A solid (11.32 g, yield 57%) with a melting point of 109-^ ll6°C with decomposition of the product is obtained. The molar purity is greater than 94% (^H NMR) .
25 ■'^H and •'•^C NMR characterization

27
^ o
J
N—4 ,N
\ /
8 7
11 ^S
\ /
10=S
Table 7

Atom 5 ^H fppm) 5 ^''C (ppm)
1 - 162.-4)!'
2 3.18 37.5
3 3.45 45.8
4 3.39 42.5
5 4.14 67.9
6 - 159.9
7 - 101.6
8 7.60 133.4
9 7.00 121.2
10 7.48 132.9
11 7.16 112.6
12 - Not observed
>WH -6.34 -

10

Solvent used: DMSO - Calibration on the signal of' DMSO at-2.4 4 ppm in ^H, 39.5 ppm in ^^C.
Infrared characterization (KBr pellet)
V (cm"^) : 2295 (function Ar-C=N^O) Mass spectrometry characterization

15 C12H13N3O3, Mw= 247.25 g/mol

28
The saitlples were analyzed by direct introduction into the mass spectrometer, using the electrospray ionization mode (DI/ESI) . ' .
Preparation of the sample
2 0 mg of the sample are dissolved in 2 ml of acetonitrile.

10

m/z\ 270 ([[M+Na]""), 517 ([2M+Na]*) -''

'

15

Example 3: Preparation of 3-methoxy-4-[2-(2-oxoimidazolidin-1-yl)ethoxyjbenzonitrile oxide
This comopound can be prepared from vanillin and 2-chloroethylimidazolidone according to the following synthesis scheme:

pathwayArK^COj, DMF
pathway B; MeONa, toluene °
pathway c: DIAD, PPhj, THF
20

CL^

2 9
a) Preparation of 3-methoxy-4-[2-(2-oxoiniidazolidin-l-
yl) ethoxyjbenzaldehydej )

5
Pathway A

1

A suspension of vanillin (30.0 g, 0.197 JJUDI) and of K2CO3 (95.4 g, 0.690 mol) in DMF (200 ml) is brought to 50°C for 15 minutes. 1-(2-Chloroethyl)imidazolidin-2-one
10 (44.0 g, 0.296 mol, purity > 90%) in DMF (30 ml) is added portionwise to this suspension. The reaction medium is heated to 90°C (Tbath) and this temperature is maintained for approximately 4 hours. The reaction medium is brought back to ambient temperature and then
15 water (1.25 1) is added. The product is extracted with CH2CI2 (400 ml, 4 times 100 ml) . The combined organic phases arp washed with water (60 ml) and concentrated under reduced pressure, (14 mbar, 40°C). The reaction crude is diluted with Et20 (100 ml) and the suspension is
20 stirred at ambient temperature for 15-20 minutes. The precipitate obtained is filtered off, washed with Et20 (3 times with 15 ml) and dried at ambient temperature.
A .-solid (31.2 g, yield 60%) with a melting point of 130°C is obtained. 25 - The molar purity is greater than 92% (-^H NMR) .
Pathway B i
Vanillin (10.0 g, 0.066 mol) in anhydrous toluene
(250 ml) is added to a solution of sodium (1.51 g,
30 0.066 mol) in CH3OH (60 ml) . The reaction medium, under

30
an inert atmosphere, is brought to reflux and then the residual methanol is distilled off. After a return to 80-90°C, a suspension of 1-(2-chloroethyl)imidazolidin-2-one (9.28 g, 0.064 mol/ purity > 95%) in toluene 5 (50 ml) is added to the reaction medium in one step. After reaction for' 25 hours, the reaction medium is concentrated under reduced pressure (Ttath 50°C, 30 mbar)-.
* The reaction crude is taken up in CH2CI2 (150 ml) . The
unreacted vanillin is removed by extraction with an
10 aqueous 7% NaOH solution (5 times w"i'€h 30 ml) . The
combined organic phases are washed with water (4 times
50 ml) , dried under Na2S04 and evaporated under reduced
pressure (Tbath 27°C, 20 mbar) . The reaction crude
(4.81 g) is diluted with a mixture of petroleum ether
15 and EtOAc, and the precipitate obtained is filtered off.
A solid (0.91 g, yield 6%) with a melting point of 127°C is obtained. The molar purity is greater than 81% (^H NMR) . |
20 Pathway C '
The procedur? of the Mitsunobu reaction is, for example,
described in the following references: Mitsunobu, 0.;
Yamada, Y. Bull. Chem. Soc. Japan 1967, 40, 2380-2382,•
25 The Use of Diethyl Azodicarboxylate and
Triphenylphosphine in Synthesis and Transformation of Natural Products Mitsunobu, 0. Synthesis 1981, 1-28,' patent EP1149092 Bl, 2003.
A solution of diisopropyl azodicarboxylate (10.1 g, 30 0.050 mol, Aldrich)_ in anhydrous THF (KO ml) is added dropwi.se, over a period of 20 minutes, to a solution of vanillin (5.02 g, 0.033 mol), anhydrous 1-(2-hydroxy-ethyl)imidazolidin-2-one (6.38 g, 0.049 mol, Aldrich)

and PPha ,(13.1 g, 0.050 mol) in anhydrous THF (300 ml) at
i 2 C. The reaction' medium is fetirred for 14 hours at
ambient t^emperature and is then diluted with water
(150 ml). The reaction medium is concentrated under
5 reduced pressure (45 mbar, Tbath 28°C) . The aqueous phase
is extracted with EtOAc (3 times with 200 ml). The
combined organic phases are washed with a saturated
aqueous solution of NaCl and are then concentrated under
reduced pressure so as to obtain a solution of 150 ml.
10 The reaction crude in solution is pufl'tied by column
chromatography (Si02, eluant 1: EtOAc, eluant 2:
EtOAc/EtOH = 4/1, Rf of the product 0.36, Rf of PhsPO
0.71 in EtOAc: EtOH = 5:1).
A solid (6.59 g, yield 76%) with a melting point of "' 15 130°C is obtained. '5 The molar purity is greater than 88% (-^H NMR) .
The 3-methoxy-4-[2-(2-oxoimidazolidin-l-yl)ethoxy]benz-aldehyde obtained is directly used in the nextlstep without further purification.
20
^H and ^'^C NMR characterization


10

32

Table S*
No. 5 of ^H 5 of "C
atoms (ppm) (ppm)
1 9.78 191.1
2 / 129.6
3 7.34 109.6 .
4 7.48 125.6
5 7.14 112.0
6 / 14 8. T'
7 / 152.9
8 3.78 55.4
9 4.11 67.3
10 3.42 45.5
11 3.38 42.3
12 3.16 37.2
13 6.33 /
14 / 161.9
Solvent used: DMSO - Calibration on the signal of DMSO at 2.44 ppm in ^H, 39.5 ppm in ^^C.
b) Preparation of 3-methoxy-4-[2-(2-oxoimidazolidin-l-yl)ethoxy]benzaldehyde oxime

A solution of hydroxylamine (10.2 g, 0.155 mol, 50% in water, Aldrich) in EtOH (20 ml) is added to a solution of 3-methoxy-4-[2-(2-oxoimidazolidin-l-yl)ethoxy]benz-

33
aldehyde, (25.6 g, 0.097 mol) in EtOH (250 ml) at 52°C. The reaction medium is then Stirred for 4.5 hours at between 50 . and. 60°C. The reaction medium is then concentrated under reduced, pressure (Tbath = 42 °C, 5 50 mbar) so as to obtain a residue of 70-80 ml. The precipitate obtained is filtered off, washed with an EtOH/water mixture (twice 5 ml/15 ml) and dried under atmospheric pressure at ambient temperature.
A white solid (22.14 g, yield 82%) with a melting point 10 of 189°C is obtained.
The molar purity is greater than 89% (^H NMR) .
^H and ■'^•'c NMR characterization

15

OH
15
Table 9
No. atoms 5 of ^H (ppm) 5 of ^^C (ppm)
1 6.30 /
2 3.16 37.1
3 3.35 42.4
4 / 161.9
5 3.42 45.4
6 4.00 67.0
7 8 / / 148.5 148.4
9 6.93 112.8
10 7.15 108.6
11 7.01 119.9

34

12 3.72 55.2
13 / i 125.9
14 • 7.98 147.5
15 10.S2 /
Solvent used: DMSO - Calibration on the signal of DMSO at 2.44 ppm in ^H, 39.5 ppm in ^^C. .
c) Preparation of 3-methoxy-4-[2-(2-oxoimidazolidin-l-
yl)ethoxy]benzonitrile oxide
o

OMe O
10
An aqueous solution of NaOCl in water (Aldrich, > 4%' of active cl:}loride) (161 ml) is added dropwise, over a period of 10 minutes, to a suspension of 3-methoxy-4-[^-
15 (2-'Oxoimidazolidin-l-yl) ethoxy] benzaldehyde oxime (21.7 g, 0.078 mol) in CH2CI2 (950 ml) at -3°C. The reaction medium is then stirred for 20 minutes at 0°C. The organic phase is separated and the aqueous phase is extracted with CH2CI2 (4 times with 100 ml) . The combined
20 > organic phases are washed with water (3 times with 100 ml) , dried over Na2S04, and then concentrated under reduced pressure (Tbath 22°C) to 200-220 ml. The precipitate obtained is filtered off, washed with CH2CI2 (twice with 10 ml) _ and dried under atmo'spheric pressure
25 at ambient temperature.
A solid (9.13 g, yield 42%) with a melting point of 109-111°C with decomposition is obtained.

35
The molar purity is greater than 8 0% (^H NMR) . With recrystallization from EtOH, th'e purity of the compound is greater,than 90% by mass.
^H and '"'^C NMR characterization

0
K V. s
Table 11 1
10 ■^^"^o- _,
No. 8 of ^H 5 of "C
atoms (ppm) (ppm)
1 / 163.5
2 6.31 /
3 3.15 37.2
4 3.35 42.3
5 3.40 45.4
6 4.04 67.1
7 / 150.4
8 / 148.4
1
9 3.73 55.6
10 7.03 113.0
11 7.25 125.8
12 7.32 115.2
13 / 106.2
14 / Not visible
10 Solvent used: DMSO - Calibration on the signal of DMSO at
2.44 ppm in ^H, 39.5. ppm in ^^C. I

36
Infrared characterization (KBr pellet)
v(cm"^): 2305- (function Ar-C=N->0) Mass spectrometry characterization
5
C13H15N3O4, Mw= 277.27 g/mol
The samples were analyzed by direct introduction. into
the mass spectrometer, using the electrospray ionization
10 mode (DI/ESI) . ~"'
Preparation of the sample
Approximately 20 mg of sample were placed in solution in
25 ml of methanol, then diluted to 1/100 for the DI/ESI
; 15 analysis.
'^ Positive mode:
m/z: 300 ([[M+Na]""), 577 ([2M+Na]'')
I
Example 4: Preparation of (Z,E)-y-(4-(2-(2-oxo-
20 imidazolidin-1-yl)ethylcarbamoyl)benzylidene)aniline < oxide
This compound can be prepared from 4-formylbenzoic acid and 2-aminoethylimidazolidone according to the following • 25 synthesis scheme:

37

a) Preparation of 4-formylbenzoyl chloride

i

10
15.


The synthesis of this compound is described in the
following references: JANSSEN PHARMACEUTICA N.V.;
I
WO2007/53386; (2007); (A2). The melting point of the
4-formylbenzoyl chloride synthesized is in accordance with the data described in the following references: Gra'ffner-Norcjperg, Malin; Sjoedin, Karin; Tunek, Anders; Hallberg, Anders Chemical & Pharmaceutical Bulletin, 1998 vol.46, 4, p.591 - 601 and Kuhlmann; Alexander Inorganica Chimica Acta, 1979, vol.34, p.197,207 and Simonis Chemlsche Berichte, 1912, vol.45, p.1586.
b) Preparation of 4-formyl-N-[2-(2-oxoimidazolidin-l-y1)ethyl]benzamide

^ , 38
A solution of the 4-formylbenzoyl chloride (16.5 g,
0.098 mol) in dry THF (100 ml)^is added, over a period
of 30 minutes,' to a suspension of l-(2-amino-
. ethyl) imidazolidin-2-one (*12.6 g, 0.098 mol) and EtsN
5 (19.8 g, 0.195 mol) in dry THF (300 ml) at -35°C. During
the addition, the temperature of the reaction medium is
maintained between -35 and -38°C. The temperature of the
reaction medium is then slowly brought back to ambient
temperature over a period of 4 hours. The precipitate
10 obtained (mainly the expected product as a mixture with
triethylamine hydrochloride EtaN'HCl) is filtered off and
washed with THF (twice with 20 ml) . The reaction crude
is solubilized in an aqueous solution of Na2C03 (3.4 g,
0.032 mol in 40 ml of water) . The expected compound is
\ 15 extracted several times with EtOAc (total ' volume:
y 3.5 1). The combined organic phases are dried over Na2S04
and concentrated under reduced pressure (T bath = 40°C) .
A solid (5.53 g, yield 22%) with a melting poibt of 138°C is obtained. 20 The molar purity is greater than 81% (^H NMR). This ' compound is directly used in the next step without further purification.
■"^H and ^^C NMR cha!racterization
// \^ NH-\ / NH

25

Table 11
No. 5 of ^H 5 of ^^C
atoms (ppm) (ppni]|
1 10.01 192.6
2 / 137.4
3/4 7.93 128.2 +

39

129.7
5 / i 139.3
6- / 165.2
7 8.69 /
8 3.33 38.2
9 3.18 42.9
10 / 162.0
11 6.24 /
12 3.35 45.0
13 3.15 37.9*
Solvent used: DMSO - Calibration on the signal of DMSO at 2.44 ppm in ^H, 39.5 ppm in ^^C.
c) Preparation of N-phenylhydroxylamine
; 5

HO^

^NH

t

10

The synthesis of this compound from nitrobenzene is described in Organic Syntheses, Coll. Vol. 1. p. 445 (1^41); Vol.^4. p. 51 (1925).

d) Preparation of (Zy.E)-N-(4-(2-(2-oxoiinidazolidi.n-l-yl)ethylcarbamoyl)benzylidene)aniline oxide

15

40
A solution of W-phenylhydroxylamine (2.21 g, 0.020 mol) in EtOH" (10 ml) is ^ added to a solution of 4-f ormyl-i\J- [2- (2-oxoimidazolidin-l-yl) ethyl] benzamide (5.3 g, 0.020 mol) in EtOH '(50 ml). The reaction mixture 5 is brought to reflux for 4 hours and then cooled to ambient temperature. The precipitate obtained is filtered off, washed with EtOH (3 times with 5 ml) and air-dried at ambient temperature.
A white solid (4.65 g, yield 66%) with a melting point 10 of 209°C is obtained.
The molar purity is greater than 92% (-^H NMR) .
^H and ■'^^C NMR characterization

1

15

1 NH 17^ ./15
-16

"^ Table 12
No. 5 of ^H 5 of "C
atoms (ppm) (ppm)
1/2 7.50 128.9 + 129.9
3 7.87 121.3
4 / 148.1
5 8.53 132.7
6 / 133^
7 8.47 128.2
8 7.87 126.9
9 / 135.3
10 / 165.3

41

11 8.58 /
12 3.33 ^ 37.5
13 ■ 3.18 42.4
14 /• 162.1
15 6.25 /
16 3.16 37.2
17 3.36 44.5
Solvent used: DMSO - Calibration on the signal of DMSO at
» 2.44 ppm in ^H, 39.5 ppm in ^^C.
Mass spectrometry characterization 5
C19H20N4O3, Mw= 352.38 g/mol
'. The sample was analyzed by direct introduction into the
^ mass spectrometer, using electrospray as ionization mode
10 (DI/ESI).
I
Preparation of the sample:
Approximately 20 mg of sample were placed in solution ir^. 0.5 ml of DMSO + 2 4.5 ml of methanol, then diluted to 15 1/100 in methanol for the DI/ESI analysis.
Positive mode
m/z: 375 ([M+Na]""), 727 ([2M+Na]'')
> 20 Negative mode
m/z: 351 ([M-H]"), 703 ([2M-H]")

CLAIMS
1. A compound comprising at least one group Q, and
5 at least one group A linked together by at least and
preferably one "spacer" group Sp, in which:
Q comprises a dipole containing at least and
preferably one nitrogen atom,
- A comprises an associative group comprising at
10 least one nitrogen atom, "*'
- Sp is an atom or a group of atoms forming a link
between Q and A.
2; The compound as claimed in claim 1, wherein the
15 associative group is chosen from an imidazolidinyl,
'1 triazoyl, ureyl, bis-ureyl and ureidopyrimidyl group.
3. The compound as claimed in claim 1 or 2, wherein
the group A corresponds to one of the formulae (II) to
20 (VI) below':
HN. .N— Y
X
(II) . :.
I I • ,
H H
(III)
0 0.
I I I I
2 5 H H H H
(IV)
H 43
R
f^^' o
I I
H H
(V)
(VI) —
5 wherein:
R denotes a hydrocarbon-based group which can
optionally contain heteroatoms,
- X denotes an oxygen or sulfur atom, preferably an
oxygen atom.
^l 10
4. The compound as claimed in any one of claims 1 to
3, wherein the group Q comprises a nitrile oxide, nitrone
or nitrile imine function.
15 5. The compound as claimed in any one of claims 1 to
4, wherein the group Q is a group of formula (VII),
(VIII) or (IX) below
Ri O X
R2 R3
• • (VII)
20' '
R4—C=N^ O
(VIII)
R5-^C=N-^ N—Re
25 (IX)
0 4 4
in which Rl to R6 are independently chosen from a spacer
f,
group Sp, a hydrogen atom, a linear or branched C1-C20
alkyl group, -a linear or branched C3-C20 cycloalkyl group,
a linear or branched C6-C26 aryl group, and a group of
5 formula (X)
' (X)
10 in which n represents 1, 2, 3, 4 or 5 and each Y
independently represents a spacer group Sp, an alkyl
group or a halogen.
6. The compound as claimed in any one of claims 1 to
>/ 15 5, wherein the "spacer" group is a linear or branched Ci-
C24, preferably Ci-Cio, alkyl chain optionally interrupted
with one or more nitrogen or oxygen atoms, more
I
preferentially a linear Ci-Ce alkyl chain.
<
20 7. The compound as claimed in any one of claims 1 to
6, wherein tk^e group Q is a group of formula (XI) :
CNO
' - .. ^ ,
(XI) • ,
25 in which R7 and R8 independently represent a C1-C5
alkyl group or a halogen, and preferably R7 and R8
independently represent a methyl groupl or a chlorine
atom, and the group A is a group of formula (XII)
0 45
> - O
(XII).
8. The compound as claimed in any one of claims 1 to
,5 7, wherein it is chosen from the compounds of formulae
(XIII) to (XXI) below:
o-
(XIII)
t i °"
II
10 (XIV)
oiT
:
(XV)
I
^ 4 6
o-
I
M
\i A ' NH
' I o
.» O '
• (XVI)
o
I / -o-
*| (XVII)
( X V I I I )
O
(XIX) I
O"
(XX)
N
I I - ' -
HN I
(XXI)