FORMULATIONS
This invention relates to the use of certain fumarate compounds as solvents,
especially in formulations, particularly in agrochemical formulations and in environmentally
friendly formulations; and to certain novel compounds. The solvents of the present
invention are found to be particularly effective at forming stable emulsions in water.
Nowadays, the Formulation Chemist is required to address a number of
environmental criteria when developing new formulations. Ideally, a suitable solvent will
display many or all of the following properties: a low water solubility; an excellent
dissolving power for pesticides or other organic molecules; made from plant or animal
renewable resources; low skin irritation; low ecotoxicity, for example to daphnia; low
volatile organic content; and a high flash point. The compounds of the present invention
each display all or many of these properties, in particular they form stable emulsions in
water; the compounds may be used effectively as solvents.
Accordingly, the present invention provides the use of a compound of formula (I) as
a solvent
where R1 and R2 are each independently hydrogen, optionally substituted [i.e. substituted or
unsubstituted] Ci-i alkyl, optionally substituted [i.e. substituted or unsubstituted]
Ci_i8 alkenyl, optionally substituted [i.e. substituted or unsubstituted] C - cycloalkyl,
optionally substituted [i.e. substituted or unsubstituted] C3-8 cycloalkenyl or optionally
substituted [i.e. substituted or unsubstituted] aryl; provided that the total number of carbon
atoms in R1 and R2 is an integer from 5 to 40 inclusive, suitably from 5 to 20 inclusive. The
expression "the total number of carbon atoms in R1 and R2 is an integer from 5 to 20
inclusive" means, for example, that if R1 contains 2 carbon atoms, then R2 may contain from
3 to 18 carbon atoms.
The present invention also relates to fumarates which can act as an adjuvant to
enhance significantly the biological performance of a pesticide.
Accordingly, the present invention provides the use as an adjuvant of a compound
of formula (I) as defined above; suitably it provides the use as an adjuvant of a compound of
formula (I)
where R and R are each independently hydrogen, optionally substituted C1-18 alkyl,
optionally substituted C1-18 alkenyl, optionally substituted C - cycloalkyl or optionally
substituted C _8 cycloalkenyl; provided that the total number of carbon atoms in R1 and R2 is
an integer from 5 to 40 inclusive [suitably from 5 to 20 inclusive].
Alkyl groups and moieties are straight or branched chains. Examples are methyl,
ethyl, zso-propyl, -propyl, -butyl, sec-butyl, tert-b y , n-amyl, iso-amyl [3-methylbutyl],
n-pentyl and n-nexyl.
Alkenyl groups and moieties may be in the form of straight or branched chains and,
where appropriate, may be of either the (E)- or (Z)-configuration. Examples are vinyl and
allyl.
Cycloalkyl includes cyclyopropyl, cyclobutyl and cyclopentyl.
Cycloalkenyl includes cyclobutenyl and cyclopentenyl.
Aryl includes phenyl. Suitably aryl is phenyl.
Optional substituents on alkyl are selected from hydroxy, =0, halo, -NH2,
-C(=0)NH 2, -C(=0)OH, -0(Ci_ )alkyl and Ci_ cycloalkyl; suitably they are selected from
hydroxy1and halo.
Optional substituents on alkenyl are selected from hydroxy, =0, halo, -NH2,
-C(=0)NH 2, -C(=0)OH, -0(Ci_ )alkyl and Ci_ cycloalkyl; suitably they are selected from
hydroxyl and halo.
Optional substituents on cycloalkyl are selected from hydroxy, =0, halo and
Ci_ alkyl; suitably they are selected from hydroxyl and halo.
Optional substituents on cycloalkenyl are selected from hydroxy, =0, halo and
Ci_ alkyl; suitably they are selected from hydroxyl and halo.
Optional substituents on aryl are independently selected from Ci_ alkyl, halo, cyano,
Ci_ haloalkyl, Ci_ alkoxy, Ci_ haloalkoxy, C2_ alkenyl, Ci_ alkoxyCi_ alkylene, Ci_
alkoxyC(=0)- and Ci_ alkylsulphonyl; suitably Ci_2 alkyl; more suitably methyl.
Suitably optionally substituted aryl is suitably optionally substituted [i.e. substituted
or unsubstituted] phenyl or optionally substituted [i.e. substituted or unsubstituted] tolyl;
more suitably phenyl or tolyl; preferably phenyl. In one aspect it is optionally substituted
phenyl.
Suitably halo is chloro, fluro or bromo; more suitably chloro or fluoro.
Suitably R1 is hydrogen or C1-18 alkyl optionally substituted by one, two or three
hydroxyl groups.
Suitably R2 is C _i alkyl optionally substituted by one, two or three hydroxyl groups.
Suitably R1 is hydrogen, methyl, ethyl, linear or branched propyl, or linear or
branched butyl ; more suitably R1 is either propyl or butyl where R2 is either propyl or butyl
Suitably R2 is propyl or butyl when R1 is butyl.
Suitably R1 is butyl when R2 is also butyl; more suitably, both are n-butyl.
In one aspect of the present invention, suitably R1 is hydrogen or Ci_2 alkyl and R2 is
substituted or unsubstituted phenyl; suitably R1 is ethyl; suitably R2 is substituted phenyl.
The present invention encompasses all isomers, or mixtures of isomers, of
compounds of formula (I) and also encompasses mixtures of two or more different
compounds of formula (I).
The selection of solvents for an (agricultural) emulsion concentrate or
water-dispersed emulsion formulation is complicated. Often there is a requirement for two
different solvents. A solvent which has an aqueous solubility of at least 0.1% w/w [at the
relevant temperature] may dissolve appreciably in an agrochemical spray tank full of water,
under normal dilution or dispersion conditions [for example, at temperatures of from just
above freezing to 35°C]. Such a solvent will not form stable emulsions in water when
formulated with surfactants however it may be an effective solvent for dissolving pesticides.
Such a solvent is normally also formulated with an oil of much lower water solubility.
Solvents which have aqueous solubility values below 0.1%w/w [at the relevant temperature]
are used along with a solvent with the above higher aqueous solubility in order to be able to
prepare stable emulsions. The solvent with the low water solubility is normally a poor
solvent for dissolving pesticides. The surprising finding about the fumarate solvents of the
present invention is that they have a low water solubility yet they are also good solvents for
pesticides. This fact is amply displayed in the data given in the Examples.
Table 1 provides structures of suitable compounds of formula (I).
Table 1
1.31 CH3CH2CH2CH2CH2 CH3CH2
1.32 CH3CH2CH2CH2CH2 CH3CH2CH2
1.33 CH3CH2CH2CH2CH2 CH3CH2CH2CH2
1.34 CH2=CHCH 2CH2CH2 CH3
1.35 CH3CH2CH2CH2CH2CH2 H
1.36 CH3CH2CH2CH2CH2CH2 CH3CH2
1.37 CH2=CHCH2CH2CH 2CH2 CH3CH2CH2
1.38 CH3CH=CHCH 2CH2CH2 CH3
1.39 CICH2CH2CH2CH2CH2CH2 CH3CH2
1.40 CH3(CH 2)7CH=CH(CH 2 ) 8 CH3
1.41 CH3(CH 2)7CH=CH(CH 2 ) 8 CH3CH2CH2CH2
1.42 CH3(CH 2)7CH=CH(CH 2 ) 8 CH3(CH 2)7CH=CH(CH 2 ) 8
1.43 Phenyl H
1.44 Phenyl CH3
1.45 Phenyl Phenyl
Suitably the invention provides the use of a compound of formula (I) in an
agrochemical formulation.
Many, but not all, of the compounds used by the present invention are novel.
Therefore in a further aspect, the present invention provides a compound of formula
(I) as defined above provided that when R1 is CH3CH2CH2, (CH3)3C, (CH3)2CH,
CH3CH2CH2CH2, (CH3)2CHCH2, CH3CH2CH2CH2CH2, CH3CH 2CH2CH(OH)CH2,
CH3CH(CH3)CH2CH2, CH3CH2CH2CH2CH2 CH2, CH3CH2CH2CH(CH3)C(OH),
CH3CH2CH(CH3)CH2C(OH), CH3CH2CH2CH2CH2(CH2CH3)CH 2, hexafluoroisopropyl,
hydroxyisopropyl, cyclohexyl, cinacalcet, formoterol, HOCH 2CH2CH2SO3,
CH3CHOHCH 2SO3, CH3CH(C(CH 3) 3)CH2CH(CH3)CH 2 or CH3CH(CH 3)CH2CH2C(OH),
then R2 is not the same as R1; when R1 is CH3CH(CH 3) then R2 is not perfluorohexylethyl,
perfluorooctylethyl, (CH 3)3C, CH3CH(CH3)CH2 or cyclohexyl; when R1 is cyclohexyl then
R2 is not CH3CH(CH3)CH2 or (CH3)3C; and when R1 is hydrogen then R2 is not stearyl.
The compounds of the invention may be used in a variety of applications (including
agrochemical formulations), particularly as solvents. These solvents may be used with a
wide variety of materials, including herbicides, fungicides, acaricides, nematicides,
insecticides and plant growth regulators.
The compounds of the invention may be used to formulate solutions of a variety of
materials, including agrochemicals, which may be formulated as emulsion or dispersion
concentrates, emulsions in water or oil, microencapsulated formulations, aerosol sprays or
fogging formulations; and these may be further formulated into granular materials or
powders, for example for dry application or as water-dispersible formulations. Any
solutions so formed may also be used directly on soil or plants or in other non-agrochemical
applications.
Examples of suitable applications include paper making, water treatment, forestry
applications, public health treatments, use in municipal pools and other water courses, in
applications near rivers, lakes, reservoirs or seas and in applications where release to the
atmosphere has to be minimised or controlled and where damage to the atmosphere is not
desirable. Examples include use in exterior and interior paints, coatings, varnishes, waxes or
other protectant layers or opacifiers, colourants or screens; in dyeing, pigmentation or the use
of inks; in cleaning products designed for the home, garden or industrial applications; and in
soap or detergent applications for industrial, home or environmental usage. The compounds
of the present invention may also be used in shampoos, household detergency and in
household cleaners [for example oven cleaners and surface cleaners].
The compounds of the present invention have exceptional dissolving power for a
wide variety of agrochemicals, pharmaceuticals and other commercially valuable
compounds, plus the dissolving power also extends to dissolution of dirt, grease or waxes.
The invention is illustrated by the following Examples in which:
g = grammes °C = degrees centigrade
N/A = not available
Unless otherwise stated, each concentration is expressed as percentage by weight.
EXAMPLE 1
This Example demonstrates the low water solubility of (E)-but-2-enedioic acid
di -butyl ester. Typically, solvents which have aqueous solubilities of about (or at least)
0.1% w/w [at the relevant temperature] can dissolve appreciably in agrochemical spray tanks
under normal dilution conditions [for example, temperatures of from just above freezing to
35°C]. These solvents do not form stable emulsions in water when used by themselves.
Solvents such as acetophenone are normally formulated with an oil of much lower water
solubility. For example, solvents which have aqueous solubility values typically below
0.1%w/w [at the relevant temperature] are suitable for preparing emulsions. Table 2
provides water solubilities for a number of solvents at 25°C. Saturated solutions of each
solvent in deionised water were prepared by leaving excess solvent in contact with water for
a period of at least two weeks. After this time a sample of the water was analysed
chromatographically to determine the concentration of solvent present.
Table 2
EXAMPLE 2
In this Example several solvents of the present invention were used to dissolve
isopyrazam. The results show that these are effective solvents for this agrochemical. A
glass vial was approximately one eighth filled with an active ingredient and then solvent was
added until the vial was approximately one third full. The resultant sample was mixed with a
Whirlimixer™ and was then stored at 25°C. The sample was checked every few days; if
there was no solid active ingredient present then additional active ingredient was added; if
there was no liquid remaining then additional solvent was added. This procedure was
repeated until the sample had equilibrated for 4 weeks following the final addition of either
active ingredient or solvent. The supernatant liquid layer was then analysed by gas
chromotography for active ingredient concentration; the solubilities of isopyrazam in several
solvents are given in Table 3 :
Table 3
EXAMPLE 3
This Example shows that the solvents of the present invention are particularly
effective at solubilising pesticides. Tables 4a and 4b show the solubility of the pesticides
azoxystrobin, difenoconazole, isopyrazam, cyproconazole, chlorothalonil and bicyclopyrone
in the solvent (E)-but-2-enedioic acid dibutyl ester. For comparison the solubilities in a
series of commonly used, low water solubility solvents are also tabulated. The data show
that in most cases the (E)-but-2-enedioic acid dibutyl ester was a more effective solvent.
Solubilities are quoted as percentage w/w at 20°C.
Table 4a
Table 4b
EXAMPLE 4
This Example shows that (E)-but-2-enedioic acid dibutyl ester may act as an adjuvant
to enhance significantly the biological performance of a pesticide. The weed species Setaria
Viridis (SETVI), Lolium Perenne (LOLPE), Avena Fatua (AVEFA) and Alopecurus
Myosuroides (ALOMY) were grown under glass house conditions and sprayed with the
herbicide pinoxaden at a rate of 7.5 grams of pesticide per hectare. Weeds were treated with
pinoxaden in the absence of (E)-but-2-enedioic acid dibutyl ester (as a control) and also with
(E)-but-2-enedioic acid dibutyl ester added to the spray-tank at a concentration of 0.2% by
volume. After both 14 and 2 1 days the efficacy of the herbicide was assessed based on the
percentage of the weeds that had been killed. Three replicates were used in all cases. The
average percentage of weeds killed is quoted in Table 5 for each weed species either with the
adjuvant or without (control). Results have been averaged across three replicates. The
standard deviation for each result is shown in brackets after the result. The results in Table 5
show that at a confidence level of 95% the solvent-containing system was found to be more
efficacious than the adjuvant-free formulation.
Table 5
EXAMPLE 5
This Example shows that (E)-but-2-enedioic acid dibutyl ester can act as an adjuvant
to enhance significantly the biological performance of a pesticide. The weed species
Polygonum Convolvulus, Digitaria Sanguinalis, Brachiaria Decumbens and Amaranthus
Tuberculatus were grown under glass house conditions and sprayed with the herbicide
mesotrione at rate of 45 grams of pesticide per hectare. Weeds were treated with the
mesotrione in the absence of (E)-but-2-enedioic acid dibutyl ester (as a control) and also with
(E)-but-2-enedioic acid dibutyl ester added to the spray-tank at a concentration of 0.2%v/v.
After 14 and 2 1 days the efficacy of the herbicide was assessed based on the percentage of
the weeds that had been killed. Three replicates were used in all cases. The performance of
the solvent was assessed by averaging the three replicates at each time period and for each
weed. The standard deviation for each result is shown in brackets after the average
percentage weed kill. The results in Table 6 show that at a confidence level of 95% the
solvent-containing system was found to be more efficacious than the adjuvant-free
formulation.
Table 6
EXAMPLE 6
This Example describes how certain ethyl fumarates according to the present invention were
prepared; for each of these fumarates, R1 is ethyl; and R2 is a substituted phenyl [derived
from the corresponding phenol]. To a solution of the relevant phenol (3.3 mmol) in
dichloromethane (2.0ml) at 0°C was added a solution of triethylamine (0.47ml) in
dichloromethane (2.0ml) followed by a solution of ethyl fumaryl chloride (500mg) in
dichloromethane (2.0ml). The reaction mixture was stirred at 0°C until completion of the
reaction and then the solvent was evaporated. The residue was partitioned between 2M
K2C0 and ethylacetate, the organics were evaporated to dryness and the crude product was
purified by flash chromatography on lOg silica cartridges using ethylacetate /hexane as
eulent. Confirmation that the required ethyl fumarate had been prepared was made by NMR
spectroscopy {1H NMR (400 MHz, CDC13 )}. The compounds tabulated, with their NMR
data, in Table 7 were each prepared in this manner. In the Table, conventional terminology
is used; for example, m=multiplet; s=singlet; d=doublet; dd=double doublet; t=triplet; q=
quartet. Each compound of Table 7 is a compound of formula (I) where R1 is ethyl and R2 is
as defined in Table 7.
Table 7
7.10 (2H, d), 7.05 (2H, s), 6.90
(2H, d), 4.30 (2H, q), 3.80 (3H, s),
1.35 (3H, t )
7.00 (2H, s), 6.80 (2H, d), 6.60
(IH, s), 4.30 (2H, q), 3.80 (3H, s),
1.35 (3H, t )
7.75 (IH, s), 7.60 (lH, d), 7.25
(IH, d), 7.10 (2H, s), 4.35 (2H, q),
1.35 (3H, t )
7.50 (IH, s), 7.30 (IH, m), 7.15
(IH, d), 7.05 (2H, s), 4.30 (2H, q),
1.35 (3H, t )
7.55 (2H, d), 7.45 (IH, s), 7.40-
7.30 (IH, m), 7.05 (2H, s), 4.30
(2H, q), 1.35 (3H, t )
8.00 (2H, d), 7.40 (2H, d), 7.05
(2H, s), 4.30 (2H, q), 3.10 (3H, s),
1.35 (3H, t )
7.30-7.20 (3H, m), 7.10 (IH, d),
7.05 (2H, s), 5.95-5.85 (IH, m),
5.10-5.00 (2H, m), 4.30 (2H, q),
3.30 (2H, d), 1.35 (3H, t )
7.25 (IH, s), 7.20 (lH, d), 7.05
(2H, s), 7.00 (IH, d), 4.30 (2H, q),
2.15 (3H, s), 1.35 (3H, t )
q),
q),
q),
s),
(2H,
d)

CLAIMS
1. A formulation comprising a compound of formula (I)
where R1 and R2 are each independently hydrogen, optionally substituted C1-18 alkyl,
optionally substituted C1-18 alkenyl, optionally substituted C - cycloalkyl, optionally
substituted C3-8 cycloalkenyl or optionally substituted aryl; provided that the total
number of carbon atoms in R1 and R2 is an integer from 5 to 40 inclusive.
2. A formulation as claimed in claim 1 where the formulation is an emulsifiable
concentrate or emulsion.
3. A formulation as claimed in claim 1 or 2 where the formulation is an agrochemical
formulation.
4. A formulation as claimed in claim 1, 2 or 3 provided that the total number of carbon
atoms in R1 and R2 is an integer from 5 to 20 inclusive.
5. A formulation as claimed in claim 1, 2, 3 or 4 where optionally substituted aryl is
substituted or unsubstituted phenyl or substituted or unsubstituted tolyl.
6. A formulation as claimed in claim 1, 2, 3, 4 or 5 where R1 is hydrogen or C1-18 alkyl
optionally substituted by one, two or three hydroxyl groups.
7. A formulation as claimed in claim 1, 2, 3, 4, 5, or 6 where R2 is C3_is alkyl optionally
substituted by one, two or three hydroxyl groups.
8. A formulation as claimed in claim 1, 2, 3, 4, 5, 6 or 7 where R1 is hydrogen, methyl,
ethyl, linear or branched propyl, or linear or branched butyl.
9. A formulation as claimed in claim 1, 2 or 3 where R2 is propyl or butyl and R1 is butyl.
10. A formulation as claimed in claim 1, 2 or 3 where R1 is hydrogen or Ci_2 alkyl and R2
is substituted or unsubstituted phenyl.
11. A compound of formula (I)
where R1 and R2 are each independently hydrogen, optionally substituted Ci_is alkyl,
optionally substituted Ci_is alkenyl, optionally substituted C - cycloalkyl or optionally
substituted C _8 cycloalkenyl; provided that the total number of carbon atoms in R1 and
R2 is an integer from 5 to 40 inclusive; and provided that when R1 is CH CH2CH2,
(CH3) C, (CH )2CH, CH CH2CH2CH2, (CH )2CHCH2, CH CH2CH2CH2CH2,
CH CH2CH2CH(OH)CH 2, CH CH(CH )CH2CH2, CH CH2CH2CH2CH2 CH2,
CH CH2CH2CH(CH )C(OH), CH CH2CH(CH )CH2C(OH),
CH CH2CH2CH2CH2(CH2CH )CH2, hexafiuoroisopropyl, hydroxyisopropyl,
cyclohexyl, cinacalcet, formoterol, HOCH 2CH2CH2S0 , CH CHOHCH 2S0 ,
CH CH(C(CH ) )CH2CH(CH )CH2 or CH CH(CH )CH2CH2C(OH), then R2 is not
the same as R1; when R1 is CH CH(CH ) then R2 is not perfluorohexylethyl,
perfluorooctylethyl, (CH ) C, CH CH(CH )CH2 or cyclohexyl; when R1 is cyclohexyl
then R2 is not CH CH(CH )CH2 or (CH ) C; and when R1 is hydrogen then R2 is not
stearyl.
A compound of formula (I) as claimed in claim 11 provided that the total number of
carbon atoms in R1 and R2 is an integer from 5 to 20 inclusive.
A compound of formula (I) as claimed in claim 11 or 12 where optionally substituted
aryl is substituted or unsubstituted phenyl or substituted or unsubstituted tolyl.
A compound of formula (I) as claimed in claim 11, 12 or 13 where R1 is hydrogen or
Ci_i8 alkyl optionally substituted by one, two or three hydroxyl groups.
15. A compound of formula (I) as claimed in claim 11, 12, 13 or 14 where R2 is C _i alkyl
optionally substituted by one, two or three hydroxyl groups.
16. A compound of formula (I) as claimed in claim 11, 12, 13, 14 or 15 where R1 is
hydrogen, methyl, ethyl, linear or branched propyl, or linear or branched butyl.
17. A compound of formula (I) as claimed in claim 11 where R2 is propyl or butyl and R1
is butyl.
18. A compound of formula (I) as claimed in claim 11, 12 or 13 where R1 is hydrogen or
Ci_2 alkyl and R2 is substituted or unsubstituted phenyl.