FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10; rule 13)
TITLE OF THE INVENTION “IMPROVED PROCESS FOR THE PREPARATION OF PYRETHROIDS”
APPLICANT
1) ENDURA S.P.A. of Viale Pietramellara, 5
40121 Bologna, Italy; Italian;
2) SOLEX CHEMICALS PRIVATE LTD.
of Suite 11, A Wing at Apeejay Business Center, Apeejay House, Block A, 8th Floor, 15, Park Street, Kolkata 700016, West Bengal, India; Indian
INVENTORS
Valerio Borzatta of Via Bellettini, 20
40127 Bologna, Italy; Italian,
Elisa Capparella of Via Dradi, 31
48123 Ravenna, Italy; Italian,
Lucio Bassetti of Via Cormons, 18
48121 Ravenna, Italy; Italian,
Giuliano Zambonin of V.le Lungomare 67/A
48122 Marina di Ravenna, Italy; Italian,
Somnath Goswami of Somaipur, Gushkara,
District: Burdwan, Pin-713128, West Bengal, India; Indian
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed

FIELD OF THE INVENTION
The present invention relates to an improved and ecofriendly process for the preparation of halogenated cyclopropanecarboxylic acid ester of tetrafluorobenzyl alcohol and its derivatives in all stereochemical configuration as well as their mixtures.
BACKGROUND AND PRIOR ART
The halogenated cyclopropanecarboxylic acid ester of tetrafluorobenzyl alcohol and its derivatives are known and they are effectively active against a wide spectrum of insect species. Among the halogenated cyclopropanecarboxylic acid ester of tetrafluorobenzyl alcohol and its derivatives, different commercial products can be mentioned such as Transfluthrin, Fenfluthrin, Meperfluthrin , Heptafluthrin and Tefluthrin.
The preparation process is based on the condensation of the chloride of the suitable halogenated cyclopropanecarboxylic acid with the suitable fluorine alcohol unsubstituted or substituted with the suitable alkyl or alkoxyalkyl moiety. In US4,889,872 according to the disclosed variant (a), transfluthrin is prepared by reacting (+)1R-trans-permethric acid chloride with 2,3,5,6-tetrafluorobenzyl alcohol at temperatures between 20°C and 100°C in the presence or in the absence of a solvent and, if appropriate, in the presence of an acid binding agent. In EP779269, transfluthrin is obtained by azeotropic esterification of (+) 1R-trans-permethric acid with 2,3,5,6-tetrafluorobenzyl alcohol in toluene and an acid catalyst so as to get the azeotropic distillation of water formed during the reaction. In Indian Patent 225306, a process for preparing transfluthrin is described. Specifically the process comprises two steps: step 1) chlorination of (+)1R-trans-permethric acid with thionyl chloride and step 2) condensation of (+)1R-trans-permethric acid chloride with 2,3,5,6-tetrafluorobenzyl alcohol in the presence of toluene as organic solvent.
In Indian Patent 239904 a method for the preparation of transfluthrin is described. Such a method comprises a first step of chlorinating (+)1R-trans-permethric acid with at least one chlorinating agent to form (+)1R-trans-permethric acid chloride,

wherein such chlorinating agent can be thionyl chloride, phosphorous trichloride, phosphorous pentachloride or elemental chlorine. The first step can be carried out in the presence of a solvent. The second step is a condensing step of (+)1R-trans-permethric acid chloride with 2,3,5,6-tetrafluorobenzyl alcohol, preferably in the presence of a solvent, more preferably toluene. When the condensation step is carried out without a solvent, the patent provides for a stirring step in order to drive out the ensuing gasses. The method provides also for a further step of purifying the crude product to obtain transfluthrin. Such a purification step comprises the treatment of the crude product in a solvent, for instance through steam distillation.
In US4,275,250 Fenfluthrin is obtained by condensation of permethric acid chloride and 2,3,4,5,6-pentafluoro benzyl alcohol by eliminating the hydrochloric acid formed during the reaction under vacuum.
In CN101580471 Meperfluthrin is obtained by condensation of 2,3,5,6-tetrafluoro-(4-methoxymethyl)benzyl alcohol with (1R)-trans-permethric acid chloride in toluene in the presence of pyridine at 20 °C .
In CN101367730 , Heptafluthrin is obtained by transesterification of a suitable alkyl 3-(3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate and 2,3,5,6-tetrafluoro-(4-methoxymethyl)-benzyl alcohol in an organic solvent in the presence of titanate catalyst at 80-150°C .The used titanate catalyst is represented by the formula Ti(OR)4.
In US7,312,366 Tefluthrin is prepared by condensation of Z-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropancarboxylic acid chloride with 2,3,5,6-tetrafluoro-(4-methyl)benzyl alcohol in toluene and with pyridine as acid acceptor.
All the above cited processes of the prior art use a solvent which can result into formation of impurities. Furthermore, the disposal of the organic solvent used usually in these processes is a problem form a legal and practical point of view.

SUMMARY OF THE INVENTION
The applicant has surprisingly found out a solvent-free process which comprises the use of suitable acid catalyst.
The invention hence concerns a process for preparing a pyrethroid of Formula (I)
wherein
X1 and X2 are, independently each other, selected from the group consisting of
hydrogen, fluorine, chlorine, bromine and trifluoromethyl with the proviso that X1
and X2 are not both hydrogen;
Z is a group of formula (IV):
wherein R1 is hydrogen or methyl, n is an integer from 1 to 5, m is (5-n), Y is
selected from the group consisting of hydrogen, (C1-C4)alkyl and (C1-
C4)alkoxy(C1-C4)alkyl,
said process comprising the steps of: a) mixing an acid of Formula (II)

with an alcohol of Formula (III)
in the presence of an acid catalyst selected from a Bronsted acid catalyst and a
heterogeneous acid catalyst, and
b) heating at a temperature of at least 100°C under vacuum.
When in the present invention:
- “a pyrethroid of Formula (I)” is stated, it is meant a pyrethroid of Formula (I) in all stereochemical configuration, as well as a mixture thereof;
- “Bronsted acid catalyst“, it is meant a chemical species able to act as a proton donor preferably an acid selected from the group consisting of p-toluenesulfonic acid or sulfuric acid.
- “a heterogeneous acid catalyst”, it is meant a catalyst where the phase of the catalyst differs from that of the reactants, preferably a perfluorinated acid catalyst such as as an example, a perfluorinated sulfonic resin sold with commercial name Nafion H ® by DuPont and a perfluorinated sulfonic resin sold with commercial name Aquivion PFSA ® by Solvay
The process of the invention represents a substantial improvement in comparison with the processes of the prior art, allowing to get yields higher than 90% and very good purity. Advantageously, the process of the invention doesn’t use any solvent during the reaction, thus allowing to lower environmental impact, specifically compared with processes using chloride solvents. A further great advantage of the invention, is that no column is needed to separate the byproducts (purification) from the main product.

DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns a process for preparing a pyrethroid of Formula (I)
wherein
X1 and X2 are, independently each other, selected from the group consisting of
hydrogen, fluorine, chlorine, bromine and trifluoromethyl with the proviso that X1
and X2 are not both hydrogen
Z is a group of Formula (IV):
wherein R1 is hydrogen or methyl, n is an integer from 1 to 5, m is (5-n), Y is
selected from the group consisting of hydrogen, (C1-C4)alkyl and (C1-
C4)alkoxy(C1-C4)alkyl,
said process comprising the steps of: a) mixing an acid of Formula (II)

with an alcohol of Formula (III)
in the presence of an acid catalyst selected from a Bronsted acid catalyst and a
heterogeneous acid catalyst; and
b) heating at a temperature of at least 100°C under vacuum.
In the present invention the Bronsted acid catalyst of step a) is preferably selected
from the group consisting of p-toluensulfonic acid or sulfuric acid. When in the
present invention a heterogeneous acid catalyst is used, a perfluorinated acid
catalyst such as a perfluorinated sulfonic resin such as a perfluorinated sulfonic
resin sold with commercial name Nafion H ® by DuPont and a perfluorinated
sulfonic resin sold with commercial name Aquivion PFSA ® by Solvay are
preferably used. Advantageously, when a heterogeneous acid catalyst is used, the
process of the invention is a continuous process or can be carried out by
continuous flux.
X1 and X2 of Formula (I) and of Formula (II) are, independently each other,
selected from the group consisting of hydrogen, chlorine, trifluoromethyl with
the proviso that X1 and X2 are not both hydrogen. More preferably, X1 and X2 are
both chlorine atoms.
Z of Formula (I) or of Formula (III) is a group of formula (IV):
wherein R1 is preferably hydrogen, n is an integer from 4 to 5, m is 0 or 1, Y is hydrogen, methyl or methoxymethyl. More preferably R1 is hydrogen, n is 4, m is 1, Y is hydrogen.
Advantageously the reaction is carried out by firstly mixing the acid of formula (II) with the alcohol of formula (III) and then by heating the mixture to

temperature of at least 100°C under vacuum to distill off the water formed during
the condensation reaction.
In a preferred embodiment, a nitrogen flow can be used during the heating step b)
to facilitate the removal of the reaction water.
The crude pyrethroid of formula (I) so obtained, is then washed to eliminate the
acid catalyst and distilled under the suitable vacuum
The ratio of the acid of formula (II) to the alcohol of formula (III) in step a) is
preferably in the range from (0.9 to 1.2) of the acid of Formula (II) to (1.2 to 1.0)
equivalents of alcohol of Formula (III), more preferably from (0.95 to 1.1)
equivalents to ( 1.1 to 1.0) equivalents.
The acid catalyst is preferably p-toluenesulfonic acid, sulfuric acid or a
perfluorinated acid catalyst such as a perfluorinated sulfonic resin such as a
perfluorinated sulfonic resin sold with commercial name Nafion H ® by DuPont
and a perfluorinated sulfonic resin sold with commercial name Aquivion PFSA ®
by Solvay.
More preferably, the acid catalyst is a Bronsted acid catalyst, still more preferably,
p-toluenesulfonic acid or sulfuric acid.
The amount of the Bronsted acid catalyst is preferably in the range from 0.15 to
0.005 eq.. with respect to the alcohol of Formula(III), more preferably from 0.1 to
0.005 eq., still more preferably from 0.1 to 0.01 eq.
The vacuum used to remove the reaction water is preferably in the range from 54
kPa to 6.7 kPa , more preferably from 27kPA to 13 kPA.
A nitrogen flow can be preferably used to facilitate the removal of the reaction
water, the nitrogen flow is preferably in the range from 400 ml/min to 20 ml/min,
more preferably from 300 ml/min to 60 ml/min, still more preferably from 250
ml/min to 100 ml/min.
Advantageously, in the preferred and more preferred embodiments the purity of
the final compound is higher.
The heating step b) allows the reaction and so the condensation of the acid of
formula(II) to the alcohol (III) and it is carried out at a temperature of at least

100°C. Such a temperature is preferably in the range from 160°C to 100°C, being the more preferred range from 130°C to 100°C.
The present invention is illustrated by way of examples, which, however, should not be construed to limit the scope of the invention.
EXAMPLE 1
Synthesis of (2,3,5,6)-tetrafluorobenzyl-(1R,3S)-3-(2,2-dichlorovinyl)-2,2-
dimethyl-1-cyclopropancarboxylate (Transfluthrin)
In a three necked bottom flask with a stirrer, 31.0 g (0.147 moles) of 1R-trans permethric acid with a purity of 99.3% (% w/w) was added to 27.0 g (0.147 moles) of 2,3,5,6-tetrafluorobenzyl alcohol with a purity of 98.2% (%w/w) and to 2.8 g ( 0.0147moles) of p-toluensulfonic acid monohydrate.
The mixture was heated to 120°C under stirring and under vacuum of 17kPA . Nitrogen was then fluxed at 130 ml/min. The mixture was then cooled to room temperature, added with 60 ml of toluene, washed with an solution of 5% (%w/v) of sodium carbonate in water, The organic solution was separated and the organic solvent evaporated at 40°C/0.7kPa .
54.5 g of a crude product with a purity of 98% (% w/w) was obtained (yield 97.9%)
1H-NMR (400 MHz, CDCl3): 1.18 (s, 3H ), 1.28 (s, 3H ); 1.60 (d, 1H, 3J = 5.2 Hz), 2.25 (dd, 1H, 3J = 8.4 Hz, 3J = 5.2 Hz ), 5.24 (s, 2H ), 5.58 (d, 1H, 3J = 8.4 Hz ), 7.10 (m, 1H ).
13C-NMR (100 MHz, CDCl3): 19.96 (CH3 ), 22.46 (CH3 ), 29.34 (Cq ), 33.17 (CH ), 34.28 (CH ), 53.80 (CH2 ), 106.71 (CH, 2J(C,F) = 22 Hz ), 115.17 (Cq, 2J(C,F) = 17 Hz ), 122.36 (Cq ), 126.61 (CH ), 144.05 (Cq, 1J(C,F) = 59 Hz, 2J(C,F) = 18 Hz ), 146.54 (Cq, 1J(C,F) = 54 Hz, 2J(C,F) = 23 Hz ), 170.38 (Cq)

EXAMPLE 2
Synthesis of (2,3,4,5,6)-pentafluorobenzyl-(1R,3S)-3-(2,2-dichlorovinyl)-2,2-dimethyl-1-cyclopropancarboxylate (Fenfluthrin)
Following the same procedure as in Example 1, Fenfluthrin was prepared starting
from 31.0 g (0.147 moles) of 1R-trans permethric acid with a purity of 99.3% (%
w/w) , 29.5 g (0.147 moles) of 2,3,4,5,6 pentafluorobenzyl alcohol, with a purity
of 98% (% w/w) and to 2.8 g ( 0.0147moles) of p-toluensulfonic acid
monohydrate by heating the mixture at 130°C under a vacuum of 20kPa and a nitrogen flow of 150 ml/min
After the work up 56,2 g of a rough product with a purity of 98% (% w/w) was obtained (yield 96.3%)
1H-NMR (400 MHz, CDCl3): 1.18 (s, 3H), 1.28 (s, 3H); 1.59 (d,1H, 3J = 5.6 Hz,), 2.24 (dd, 1H, 3J = 8.4 Hz, 3J = 5.6 Hz ),5.24 (s, 2H), 5.59 (d, 1H, 3J = 8.4 Hz).
13C-NMR (100 MHz, CDCl3): 19.92 (CH3 ), 22.41 (CH3), 29.39 (Cq,), 33.23 (CH ), 34.23 (CH ), 53.32 (CH2 ), 109.54 (CH, 2J(C,F)= 21.1 Hz ), 137.49 (Cq, 2J(C,F) = 251.6 Hz ), 141.75 (Cq, 2J(C,F) =254.2 Hz ), 145.71 (Cq, 2J(C,F) = 238.5 Hz ), 122.39 (Cq ),126.56 (CH ), 170.33 (Cq ).
EXAMPLE 3
Synthesis of [2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl-(1R,3S)-3-(2,2-
dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate (Meperfluthrin)
Following the same procedure as in Example 1, Meperfluthrin was prepared
starting from 31.0 g (0.147 moles) of 1R-trans permethric acid with a purity of
99.3% (% w/w) , 33.5 g (0.147 moles) of 2,3,5,6 tetrafluoro-4-
(methoxymethyl)benzyl alcohol, with a purity of 98.2% (% w/w) and to 2.8 g ( 0.0147moles) of p-toluensulfonic acid monohydrate by heating the mixture at 130°C under a vacuum of 17kPa and a nitrogen flow of 180 ml/min
After the work up 60.6 g of a rough product with a purity of 97.8% (% w/w) was obtained (yield 97.1%) 1H-NMR (400 MHz, CDCl3): 1.17 (s, 3H), 1.27 (s, 3H ); 1.59 (d,

1H, 3J = 5.2 Hz), 2.24 (dd, 1H, 3J = 8.4 Hz, 3J = 5.2 Hz ), 3.39 (s, 3H ), 4.57 (s, 2H ), 5.23 (s, 2H ), 5.58 (d, 1H, 3J = 8.4 Hz ).
13C-NMR (100 MHz, CDCl3): 19.94 (CH3), 22.42 (CH3), 29.32 (Cq,), 33.16 (CH), 34.27 (CH), 53.69 (CH2 ), 58.46 (CH3), 61.36 (CH2 ), 114.63 (Cq, 2J(C,F) = 16.9 Hz ), 116.95 (Cq, 2J(C,F) =17.1 Hz ), 122.29 (Cq ), 126.63 (CH ), 145.09 (Cq, 2J(C,F) =246.7 Hz ), 170.33 (Cq).
EXAMPLE 4
Synthesis of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl-1RS,3RS;1RS,3SR)-2,2-dimethyl-3-[(1Z)-3,3,3-trifluoroprop-1-enyl]-cyclopropanecarboxylate (Heptafluthrin)
Following the same procedure as in Example 1, Heptafluthrin was prepared
starting from 32.4 g (0.147 moles) of (1RS,3RS;1RS,3SR)-2,2-dimethyl-3-[(1Z)-3,3,3-trifluoroprop-1-enyl] -cyclopropanecarboxylic acid with a purity of 98.8% (% w/w) , 33.5 g (0.147 moles) of 2,3,5,6 tetrafluoro-(4-methoxymethyl)benzyl alcohol, with a purity of 98.2% (% w/w) and to 2.8 g ( 0.0147moles) of p-toluensulfonic acid monohydrate by heating the mixture at 120°C under a vacuum of 21kPa and a nitrogen flow of 180 ml/min
After the work up 60.8 g of a rough product with a purity of 97.5% (% w/w) was obtained (yield 97.4%)
1H-NMR (400 MHz, CDCl3): 1.18 (s, 3H ), 1.27 (s, 3H ); 1.67 (d, 0.8H, 3J = 5.2 Hz ), 1.85 (d, 0.2H, 3J = 3.2 Hz ), 2.41 –2.45 (m, 0.8H), 2.78 – 2.88 (m, 0.2H ), 3.39 (s, 3H ), 4.57(s, 2H ), 5.24 (s, 2H ), 5.23 – 5.69 (m, 2H ).
13C-NMR (100 MHz, CDCl3): 20.02 (CH3), 21.96 (CH3 ), 30.13 (Cq), 31.50(CH), 35.69 (CH ), 53.65 (CH2), 58.43 (CH3), 61.33 (CH2 ), 114.63 (Cq, 2J(C,F) = 16.6 Hz ), 116.97 (Cq, 2J(C,F) =17.6 Hz ), 120.39 (CH, 2J(C,F) = 33.7 Hz ), 123.13 (Cq, 1J(C,F) = 269.8 Hz ), 138.96 (CH, 3J (C,F) = 5.4 Hz ), 145.10 (Cq, 1J (C,F) = 246.6Hz ), 170.08 (Cq ).

EXAMPLE 5
Synthesis of (2,3,5,6)-tetrafluorobenzyl-(1R,3S)-3-(2,2-dichlorovinyl)-2,2-
dimethyl-1-cyclopropancarboxylate (Transfluthrin)
Following the same procedure as in Example 1, 31.0 g (0.147 moles) of 1R-trans
permethric acid with a purity of 99.3% (% w/w) was added to 27.0 g (0.147
moles) of 2,3,5,6-tetrafluorobenzyl alcohol with a purity of 98.2% (%w/w) and to
12.0 g ( 0.0156 eq of acid capacities . ) of Aquivion PFSA ®
The mixture was heated to 110°C under stirring and under vacuum of 17kPA .
Nitrogen was then fluxed at 120 ml/min. The mixture was then cooled to room
temperature, added with 60 ml of toluene, washed with an solution of 5% (%w/v)
of sodium carbonate in water, The organic solution was separated and the organic
solvent evaporated at 40°C/ 0.3kPa.
After the work up 47.2 g of a rough product with a purity of 98.1% (% w/w) was
obtained (yield 85.1%)

WE CLAIM:
1. A process for preparing a pyrethroid of Formula (I)
wherein
X1 and X2 are, independently each other, selected from the group consisting of
hydrogen, fluorine, chlorine, bromine and trifluoromethyl with the proviso that X1
and X2 are not both hydrogen
Z is a group:
(IV)
wherein R1 is hydrogen or methyl, n is an integer from 1 to 5, m is (5-n), Y is
selected from the group consisting of hydrogen, (C1-C4)alkyl and (C1-
C4)alkoxy(C1-C4)alkyl,
said process comprising the steps of: a) mixing an acid of Formula (II)

with an alcohol of Formula (III)
in the presence of an acid catalyst selected from a Bronsted acid catalyst and a
heterogeneous acid catalyst, and
b) heating at a temperature of at least 100°C under vacuum.
2. The process according to claim 1, wherein X1 and X2 are both chlorine atoms.
3. The process according to claim 1 or 2, wherein in Z group of Formula (I) or Formula (III), R1 is hydrogen, n is an integer from 4 to 5, m is 0 or 1, Y is hydrogen, methyl or methoxymethyl.
4. The process according to anyone of claims 1-3, wherein the ratio of the acid of formula (II) to the alcohol of formula (III) in step a) is from (0.9 to 1.2) of the acid of Formula (II) to (1.2 to 1.0) equivalents of alcohol of Formula (III).
5. The process according to claim 4, wherein the ratio of the acid of formula (II) to the alcohol of formula (III) in step a) is from (0.95 to 1.1) equivalents. to ( 1.1 to 1.0) equivalents.
6. The process according to anyone of claims 1-5, wherein the acid catalyst of step a) is selected from the group of p-toluenesulfonic acid, sulfuric acid or a perfluorinated sulfonic acid resin.
7. The process according to claim 6, wherein the perfluorinated sulfonic acid
resin is a perfluorinated sulfonic resin sold with commercial name Nafion H ® by
DuPont or a perfluorinated sulfonic resin sold with commercial name Aquivion
PFSA ® by Solvay.
8. The process according to claim 6, wherein the acid catalyst is a Bronsted acid catalyst selected from p-toluenesulfonic acid and sulfuric acid.
9. The process according to claim 1, wherein the acid catalyst is a Bronsted acid catalyst and the amount of the Bronsted acid catalyst in step a) is in the range from 0.15 to 0.005 eq. with respect to the alcohol of Formula(III).
10. The process according to claim 9, wherein the amount of the Bronsted acid
catalyst in step a) is in the range from 0.1 to 0.005 eq.

11. The process according to claim 10, wherein the amount of the Bronsted acid catalyst in step a) is in the range from 0.1 to 0.01 eq.
12. The process according to claim 1, wherein the acid catalyst is a heterogeneous acid catalyst and the process of claim 1 is carried out by continuous flux.
13. The process according to anyone of claims 1-12, wherein the vacuum is in the range from 54 kPa to 6.7 kPa.
14. The process according to claim 13, wherein the vacuum is from 27kPA to 13 kPa.
15. The process according to anyone of claims 1-14, wherein a nitrogen flow is used during the heating step b).
16. The process according to claim 15, wherein the nitrogen flow is in the range from 400 ml/min to 20 ml/min
17. The process according to claim 16, wherein the nitrogen flow is in the range from 300 ml/min to 60 ml/min.
18. The process according to claim 17, wherein the nitrogen flow is in the range from 250 ml/min to 100 ml/min.
19. The process according to anyone of claims 1-18, wherein the temperature of step b) is in the range from 160°C to 100°C.
20. The process according to claim 19, wherein the temperature of step b) is in the range from 130°C to 100°C.