Field of invention
The present invention belongs to the field of organic synthesis. The invention
particularly relates to new and improved process for synthesis of intermediates
benzyl ketone (INT 1) represented by Formula I and oxirane (INT 2) represented
5 by Formula II useful as key intermediates for the synthesis of triazole fungicides
particularly Prothioconazole represented by formula III.
Background of the invention
Benzyl ketones and oxiranes are valuable key intermediates for the preparation
of triazole fungicides. One such example of triazole fungicides is prothioconazole.
10 Prothioconazole is a broad-spectrum systemic fungicide with a Triazolinedione
structure which is useful for the control of diseases caused by ascomycetes,
basidiomycetes and deuteromycetes on a variety of crops. It acts as a sterol
demethylation (ergosterol biosynthesis) inhibitor and after absorption into cells
of target organisms, it disrupts the membrane structure ultimately affecting the
15 hyphal growth and germ tube elongation.
Prothioconazole is sold in combination with numerous other fungicides, including
bixafen, spiroxamine, tebuconazole, fluoxastrobin, trifloxystrobin and fluopyram,
etc.
PROTHIOCONAZOLE
20 IUPAC name: 2-[(2RS)-2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-
hydroxypropyl]-2H-1, 2, 4-triazole-3(4H)-thione
CAS: 178928-70-6
MOLECULAR FORMULA: C14H15Cl2N3OS
MOLECULAR WEIGHT: 344.254 g/mol
25
STRUCTURE:
3
Formula III
Many methods for preparation of Prothioconazole or key intermediates for
synthesis of related active compounds are known in the prior art.
5 For instance, CN106749057A discloses intermediate compound and a method for
synthesizing prothioconazole. The method comprises: The substitution reaction
on 5,5'-dithio-bis(1,2,4-triazole) and 2-(1-chlorocyclopropyl)-3-chloro-1-(2-
chlorophenyl)-2-propanol to obtain the key intermediate compound; and
reduction of key intermediate compound to obtain the target product
10 prothioconazole this process however is not suitable for commercial scale and
metal TECP and Zn has been used for reduction.
US6271389B discloses the method for producing triazolinethione derivatives
which are known as active compounds having microbicidal, fungicidal,
properties. Triazolidinethione obtained using 2-(1-chloro-cyclopropyl)-3-(2-
15 chloro-phenyl)-2-hydroxy-propyl-1-hydrazine and 2N aqueous hydrochloric with
acetone followed by addition of potassium thiocyanate. Intermediate is further
converted to prothioconazole using isobutyl formate and formic acid. This
process is not suitable for manufacturing because high vacuum distillation
system has been used in the process.
20 US005146001 discloses the preparation of INT-1 by using zinc dust along with
toxic and expensive palladium complex bis(triphenylphosphine) palladium (II)
chloride. This prior art discloses the unstable acid chloride (1-
chlorocyclopropanecarbonyl chloride) at 150 degree Celsius and preparation of
INT-2 (oxirane) using expensive trimethylsulfoxonium chloride along with strong
4
bases such as potassium hydroxide, potassium t -butoxide and sodium
methoxide in various solvents such as dimethyl sulphoxide, acetonitrile, etc. Final
Prothioconazole obtained by this process was purified by column
chromatography, which is not a suitable option for manufacturing at industrial
5 scale.
US005099040 discloses a new process for the preparation of 1-chloro-2-(1-
chloro-cyclopropyl)-3-(2-chloro-phenyl)-propan-2-ol and/or 2-(1-chlorocyclopropyl)-2-(2-chloro-benzyl)-oxirane. comprising a) reacting in a first step, 2-
chloro-benzyl chloride with comminuted magnesium in the presence of a
10 mixture of toluene and tetrahydrofuran, in which the ratio of toluene to
tetrahydrofuran is between 65:35 and 95:5 parts by weight, at a temperature
between 0° C and 100 ℃, the ratio of 2-chlorobenzyl chloride to tetrahydrofuran
being such that between 1 and 3 moles of tetrahydrofuran are present per mol
of 2-chloro-benzyl chloride, and subsequently separating off any magnesium
15 which may still be present, and b) reacting the resulting Grignard reagent in a
second step with 1-chloro-1-chloroacetylcyclopropane of in the presence of a
mixture of toluene and tetrahydrofuran, in which the ratio of toluene to
tetrahydrofuran is between 65:35 and 95:5 parts by weight, at a temperature
between 0° C and 100° C. In this process two products formation was observed,
20 which is not suitable for preparation of oxirane (INT-2) commercially.
US5789430A discloses the Triazolyl derivatives of the formula
In which,
R
1
and R2
are identical or different and represent optionally substituted alkyl,
25 optionally substituted alkenyl, optionally substituted cycloalkyl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally substituted
5
aroxyalkyl, optionally substituted aryl or optionally substituted heteroaryl and X
represents the groups -SH, -SR3
, -SO-R
3
, -SO2-R
3
or –SO3H, in which R3
represents
alkyl which is optionally substituted by fluorine and/or chlorine, alkenyl which is
optionally substituted by fluorine and/or chlorine, optionally substituted aralkyl
5 or optionally substituted aryl, and their acid addition salts and metal salt
complexes. It further discloses a plurality of processes for the preparation of the
new substances and their use as microbicides in plant protection and materials
protection.
EP2746260A1 discloses the preparation of INT-1 from compound 5a via Grignard
10 reaction with only 61% yield. The Grignard reagent is prepared from 2-
chlorotoluene using t
BuLi as reagent which is highly pyrophoric in nature and not
suitable for plant scale. The above mentioned Grignard reaction was carried out
at -78o
C. This process in not advisable for manufacturing due to low
temperature.
15 CN 109369549 discloses the preparation of INT-2 from INT-1 by using dimethyl
sulfide and dimethyl sulfate in different organic solvents (like toluene,
dichloromethane, methanol etc).
US4913727 describes a process for producing l-chloro-2-(l-chlorocyclopropyl)-3-
(2-chlorophenyl)propan-2-ol using a highly inflammable solvent such as diethyl
20 ether. This patent also discloses reaction of l-chloro-2-(l-chlorocyclopropyl)-3-(2-
chlorophenyl)propan-2-ol with 1,2-4-triazole under basic condition. The
disadvantage of this process is that under basic condition, 1,2,4-triazole
undergoes isomerization, resulting in the formation of corresponding regioisomers as an impurity.
25 US5099040 discloses process for producing mixture of l-chloro-2-(lchlorocyclopropyl)-3-(2-chlorophenyl)propan-2-ol and 2-(2-chlorobenzyl)-2-(lchlorocyclopropyl)oxirane using a mixture of various solvent particularly a
mixture of toluene and THF, which is the disadvantage of this process as
separation of toluene from THF is not cost effective process on an industrial
6
scale.
US6262276 discloses a process for producing thiosemicarbazide, which then
admixed with isobutyl formate and formic acid to get Prothioconazole.
Formation of an isomeric impurity during the reaction of hydrazine derivatives
5 and thiocyanate in basic condition is a disadvantage of this method. Moreover,
expensive and hazardous reagents such as n
butyllithium along with sulphur were
used to construct triazolidinethione ring in 2-(lchlorocyclopropyl)-1-(2-
chlorophenyl)-3 -(1 ,2,4-triazol- 1-yl)-propan-2-ol.
WO99/18087 describes the process for preparation of 2-(l-chloro-cycloprop-l-yl)-
10 l-(2-chloro-phenyl)-3-(4, 5-dihydro- 1,2,4-triazole-5 -thiono- 1-yl)-propan-2-ol . 2-
( 1-Chlorocycloprop-l-yl)-3-(2-chloro phenyl)-2-hydroxy propyl- 1-hydrazine can
be prepared by reacting 3-chloro-2-(l-chloro cycloprop-l-yl)-l-(2-chloro phenyl)-
propan-2-ol with hydrazine hydrate in the presence of an inert organic solvents,
such as alcohol, ether or nitrile. The reaction of resulting 2-(l-chloro-cycloprop-l15 yl)-3-(2-chloro phenyl)-2-hydroxy propyl- 1-hydrazine with formaldehyde and
alkali metal thiocyanate or ammonium thiocyanate to get 2-(l-chloro cyclopropl-yl)-l-(2-chloro phenyl)-2- hydroxy-3-(l,2,4-triazolidine-5-thiono-l-yl)-propane,
which in turn reacts with oxygen in the presence of sulphur and potassium
hydroxide to obtain Prothioconazole. 2-(l-Chlorocycloprop-l-yl)-3-(2-chloro
20 phenyl)-2-hydroxy propyl- 1-hydrazine in its free state is relatively unstable, and
hence contributes to lower yield in the subsequent stages.
US2003/013890 discloses a process for preparation of 2-(l-chloro-cycloprop-l-yl)-
3-(2-chlorophenyl)-2-hydroxypropyl- 1-hydrazine using hydrazine hydrate in a
mixture of toluene and acetonitrile. Hydrochloric gas is employed to prepare
25 hydrochloride salt of 2-(l-chloro-cycloprop-l-yl)-3-(2-chlorophenyl)-2-
hydroxypropyl-l-hydrazine. Synthesis of 2-(l-chlorocycloprop-l-yl)-l-(2-
chlorophenyl)-2-hydroxy-3-(l,2,4-triazolidine-5-thionol-yl)-propane involves the
use of alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and
potassium hydroxide in presence of water and ethyl acetate, leading the
7
formation of l0-l5% impurity, which causes low yield. Use of ferric chloride for
aromatization at the last stage may lead to high iron content in the final product.
WO2019/123368 discloses a process for Prothioconazole using 2-[2-(lchlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-l,2,4-triazolidine-3–
5 throne in-presence of activated charcoal and methanol as a solvent. The
intermediate prepared using 2-(l-chloro-cycloprop-l-yl)-3-(2-chloro phenyl)-2-
hydroxypropyl- 1-hydrazine, ammonium thiocyanate, formamide, potassium
hydrogen sulphate and dichloromethane as a solvent. This process is not
suitable for plant scale manufacturing due to low boiling solvent used in the
10 process and yields are also low.
US2019/0135766 discloses a method of synthesizing prothioconazole and
optically active isomers thereof and intermediates. The method includes reacting
hydrazine with glyoxylic acid to produce a hydrazono acetic acid as an
intermediate, and then reacting the intermediate with thiocyanate to produce
15 the target product prothioconazole. The process is very specific in terms of
regioselectivity, resulting in minimum byproducts and a high product yield.
While different schemes are known for the process for synthesis of
intermediates and prothioconazole, there still exists a need to develop a
reaction scheme that confers multiple advantages particularly, higher efficacy,
20 satisfactory yield, purity and scalability.
Object of the present invention
An object of the present invention is to provide an improved method of synthesis
of benzyl ketone (1-(1- Chlorocyclopropyl)-2-(2-chlorophenylethanone)) referred
to as INT1 and represented by Formula I.
Cl
O
Cl
INT-1
25
Formula I
Another object of the present invention is to provide an improved method of
8
synthesis of oxirane (2-(1-Chlorocyclopropyl)-2-[(2-chlorophenyl)methyl]oxirane)
referred to as INT2 and represented by Formula II.
Cl
Cl
INT-2
O
Formula II
5 Yet another objective of the present invention is to provide an improved method
of synthesis of triazole fungicides particularly Prothioconazole represented by
formula III using intermediates INT 1 and INT 2.
Another object of the present invention is to provide a simple process to prepare
benzyl ketone and oxirane intermediate with high scalability without using the
10 commonly used organic solvents, thus increasing the safety of the process.
Still another object of the present invention is to provide an improved process
for synthesis of intermediates in the process of preparation of Prothioconazole
that provides high purity and excellent yield.
Summary of the present invention
15 A process for the preparation of a benzyl ketone (INT 1) of formula I below:
Formula I
wherein said process comprises steps of:
20 i) reacting 2-chloro-benzyl chloride with magnesium turnings in the
presence of diethyl ether and at least one catalyst, at a temperature
in the range of 25o
C to 35o
C to form (2-chlorobenzyl)magnesium
chloride (Grignard reagent) of formula
Cl
O
Cl
INT-1
9
ii) reacting (2-chlorobenzyl)magnesium chloride obtained in step (i)
with amides or acid chlorides or esters of general formula
5 where, R is selected from the group consisting of NMe(OMe), Cl, OMe, OEt,
NH-Cyclohex, NMe2, and morpholine in the presence of 1
Chlorocyclopropanecarboxylicacid derivatives at a temperature range of78o
C to 30o
C in the presence of toluene under inert atmosphere to obtain
benzyl ketone (INT 1).
10 In another aspect of the present invention, there is provided a process for the
preparation of an oxirane (INT 2) of formula II:
Cl
Cl
INT-2
O
comprising reacting dimethyl sulphate with an excess of dimethyl sulphide
thereby to form trimethylsulphonium methyl-sulphate and without prior
15 isolation reacting the trimethylsulphonium methyl-sulphate with INT 1 of claim 1
(1-(1-chlorocyclopropyl)-2-(2-chlorophenyl)ethanone) in the presence of any of
solid potassium hydroxide, sodium hydroxide, and sodium methoxide as a base.
In yet another aspect of the present invention, there is provided a process for
the preparation of compound 8 of formula III below:
20
Cl
Mg
Cl
R
O
Cl
10
comprising the steps:
i) reacting the compound (2-chloro-α-(1-chlorocyclopropyl)-α-(hydrazinylmethyl)
-benzeneethanol hydrochloride) with an aqueous solution of glycolic acid at a
temperature in the range of 25-30o
C to obtain 2-(2-(2-(1-chlorocyclopropyl)-3-(2-
5 chlorophenyl)-2-hydroxypropyl)hydrazono)acetic acid; and
ii) isolating the compound 2-(2-(2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-
hydroxypropyl )hydrazono)acetic acid obtained from step (i) and reacting with
sodium thiocyanate and acetic acid at a temperature in the range of 25-30o
C to
obtain compound of formula III.
10 Detailed description of the present invention
Those skilled in the art will be aware that the invention described herein is
subject to variations and modifications other than those specifically described. It
is to be understood that the invention described herein includes all such
variations and modifications. The invention also includes all such steps, features,
15 compositions and compounds referred to or indicated in this specification,
individually or collectively, and any and all combinations of any two or more of
said steps or features.
Problem Identified
The present invention deals with various factors associated with process
20 improvement, recovery reuse of solvents, cycle time reduction, using
commercially available raw materials and process optimization of
Prothioconazole (hereinafter referred as a compound 8 as shown in the reaction
scheme). According to process disclosed in US005099040 2-(1-chlorocyclopropyl)-2-(2-chloro-benzyl)-Oxirane (INT-2). 1-chloro-2-(1-chloro25 cyclopropyl)-3-(2-chloro-phenyl)-propan-2-ol and/or 2-(1-chloro-cyclopropyl)-2-
(2-chloro-benzyl)-oxirane two products formation observed by reacting the 2-
chlorobenzyl magnesium chloride with 1-chloro-1-chloroacetyl-cyclopropane at
a temp. in the range of 20-25o
C in presence of a mixture of toluene and
tetrahydrofuran as solvents. Almost 60:40 ration of product formation observed,
11
in presence of mixture of aromatic hydrocarbons such as mixture of toluene and
tetrhydrofuran. It is found that reaction was incomplete and sluggish when
tetrahydrofuran and used as a solvent. This process is neither scale up friendly
nor cost-effective at industrial scale. The present invention discloses a process
5 that uses single solvent.
According to process described in US005146001 the preparation of INT-1 by
reacting 2-chloro-benzylchloride and unstable acid chloride (1-
chlorocyclopropanecarbonyl chloride) using zinc dust along with toxic and
expensive palladium complex bis(triphenylphosphine) palladium (II) chloride. at
150o
10 C. Low purity and low yield are major disadvantages of this Step. Moreover,
present inventors have overcome this problem by using the mild regents in a
suitable solvent. Preparation of INT-2 (oxirane) reacting INT-1 using
trimethylsulfoxonium chloride along with strong bases such as potassium
hydroxide, potassium t-butoxide and sodium methoxide in various solvents such
15 as dimethyl sulphoxide, acetonitrile, etc. Final Prothioconazole obtained by this
process was purified by column chromatography, reagents used is highly
expensive, whereas the present invention uses less expensive regents for the
synthesis of INT-2 in a suitable solvent.
The process reported in US2019/0135766 for the synthesis of prothioconazole
20 involves the use of industrially viable 50% glyoxylic acid. 2-(2-(2-(1-
chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl)hydrazono)acetic acid
was prepared by reacting 2-(2-(2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-
hydroxypropyl)hydrazono)acetic acid with 50% glyoxylic acid using water and
acetonitrile as solvents at room temperature, product isolated taken as such to
25 next step with sodiumthiocyanate and acetic acid as a reaction media. Product
isolated using water and pure prothioconazole (Compound 8) obtained by
toluene purification. The process is simple but intermediate formed -chloro-α-(1-
chlorocyclopropyl)-α-(hydrazinylmethyl)-benzenethanol hydrochloride impure
and unstable in nature, which causes low yield. Quality of the Prothioconazole
12
was not up to the mark. The present invention demonstrates the process for
purification of the compound 6. Purification leads to high quality and high purity
(>98% area by HPLC) of Prothioconazole.
Solution Provided by the Present Invention
5 The present invention provides a method for producing benzyl ketone (1-(1-
Chlorocyclopropyl)-2-(2-chlorophenylethanone) referred to as INT 1 represented
by Formula I, and oxirane (2-(1-Chlorocyclopropyl)-2-[(2-
chlorophenyl)methyl]oxirane) referred to as INT 2 represented by Formula II and
Prothioconazole (Compound 8) possessing consistent purity and yield.
10 INT 1: INT-1 synthesized by two routes. In the first route γ-butyrolactone
(compound 1) in excess of thionyl chloride is treated with 3.5% (w/w) ZnCl2 for
10-22 hours, to obtain 2,4- dichlorobutanoylchloride (compound 2). Further,
compound 4 is obtained by reacting 2,4- dichlorobutanoylchloride with 2-
chlorobenzylmagneium chloride in the presence diethyl ether .Compound 4
15 undergoes cyclization reacting with ethylene glycol and sodium metal to obtain
INT-1. This process is not suitable for commercial manufacturing due to sodium
metal used in the process.
In the second route 1-chlorocyclopropanecarboxylic acid in hexane, reacting with
thionyl chloride at 40-45o
C, which is further treated with N,O20 Dimethylhydroxylamine, to form Weinreb–amide (Compound 5a) and similarly
other derivatives of 1-chlorocyclopropanecarboxylic acid is prepared and
subsequently 1-chlorocyclopropanecarboxylic acid derivatives (intermediates
5a-5g) treated with 2-chloro-benzylmagnesiumchloride however this route is
more feasible for manufacturing.
25 INT 2: According to the process described in US005146001 Preparation of benzyl
ketone and an oxirane is obtained by using expensive trimethylsulfoxonium
chloride along with strong bases in various solvents such as dimethyl sulphoxide,
acetonitrile, etc. Final Prothioconazole obtained by this process was purified by
column chromatography. The present inventors herein report the use of
13
dimethyl sulphate and dimethyl sulphide over trimethylsulfoxonium chloride for
manufacturing of INT 2 without solvent. The process of the present invention
used for the preparation of an INT 2 is simple, scalable, and reproducible at a
higher scale.
5 Prothioconazole (Compound 8):
Synthesis of fungicidal compound, Prothioconazole was carried out by using
three different routes.
Route 1: Compound 6 is reacted with ammoinumthiocyanate in ethylacetate to
form compound 7A and 7B. The desired product 7A was recrystallized using
10 methanol as solvent. Prothioconazole obtained from Compound 7A by further
treating it with isobutyl formate and formic acid. In this process, yield (59%) is
low in the intermediate stage and separation of 7A and 7B is difficult.
Route 2: Compound 10 obtained by reacting 2-(1-chlorocyclopropyl)-2-[(2-
chlorophenyl)methyl]oxirane (INT-2) with 1,2-4-triazole under basic condition.
15 The disadvantage of this process is that under basic condition, 1,2,4-triazole
undergoes isomerization, resulting in the formation of corresponding regioisomers as an impurity. Further compound 10 is reacted with sulfur and DMF as a
solvent at 145-150o
C to form Compound 8. The disadvantage of this process is
heating reaction mass with sulfur at high temperature.
20 Route 3: The process reported in US2019/0135766 for the synthesis of
prothioconazole involves the use of industrially viable 50% glyoxylic acid.
Prothioconazole prepared by 2-chloro-α-(1-chlorocyclopropyl)-α-
(hydrazinylmethyl)-benzenethanol hydrochloride treated with 50% glyoxylic acid
and water/acetonitrile, 2-(2-(2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-
25 hydroxypropyl)hydrazono)acetic acid obtained further treated with sodium
thiocyanate and acetic acid.
The process for preparation of Prothioconazole, as disclosed in the present
invention is simple, scalable, and reproducible at a higher scale. High purity of
compound 11 is achieved by recrystallization in hexane. The compound 11 taken
14
for the next reaction with sodium thiocyanate and acetic acid to obtain crude
product followed by purification with n-heptane. The purity of the compound 8
thus achieved by this process is more than >98% area by HPLC. Prothioconazole
from this route is of high purity and high yield compared to the other routes.
5 In an embodiment, the present invention discloses a novel process for the
preparation of benzyl ketone and oxirane intermediates (INT 1 and INT 2
respectively).
In an embodiment of the present invention, there is provided a process for the
preparation of Prothioconazole (compound 8) of formula III
10
wherein said process comprises the steps of:
i) reacting 1-chlorocyclopropanecarboxylic acid in hexane with thionyl
chloride at 40-45o
15 C, which is further treated with N,ODimethylhydroxylamine, to form a Weinreb–amide 1-chloro-N-methoxyN-methylcyclopropane carboxamide (Compound 5a), which subsequently
reacting with 2-chloro-benzylmagnesiumchloride (Grignard reagent) in
diethyl ether at 25-30o
C to form 1-(1-Chlorocyclopropyl)-2-(2-
20 chlorophenyl)ethanone (INT 1);
Grignard reagent is prepared from 2-chlorobenzyl chloride and without
using any hazardous, pyrophoric reagent and the Grignard reaction is
carried out at ambient temperature with high yield (>90%) for
intermediate 5a (1-chloro-N-methoxy-N25 methylcyclopropanecarboxamide).
15
i) Oxirane preparation ( INT-2) is carried out in the presence of dimethyl
sulphate with an excess of dimethyl sulphide thereby to form
trimethylsulphonium methyl-sulphate and without prior isolation reacting
5 the trimethylsulphonium methyl-sulphate with a ketone (INT-1) (1-(1-
chlorocyclopropyl)-2-(2-chlorophenyl)ethanone) in the presence of solid
potassium hydroxide or sodium hydroxide or sodium methoxide as base
and without using organic solvents generally used for oxirane preparation
reaction like toluene or dichloroethane or dichloromethane or methanol
10 with yield greater than >90%.
In an embodiment Grignard reaction is carried out with seven derivatives (5a5g) of 1-chlorocyclopropanecarboxylic acid.
15 In another embodiment, seven intermediates are selected from the group
consisting of 1-chloro-N-methoxy-N-methylcyclopropanecarboxamide (referred
to as 5a), 1-chlorocyclopropanecarbonyl chloride (referred to as 5b), methyl 1-
chlorocyclopropanecarboxylate (referred to as 5c), ethyl 1-
chlorocyclopropanecarboxylate (referred to as 5d),1-chloro-N20 cyclohexylcyclopropanecarboxamide (referred to as 5e), 1-chloro-N,Ndimethylcyclopropanecarboxamide (referred to as 5f), (1-
chlorocyclopropyl)(morpholino)methanone (referred to as 5g).
In another embodiment compound 8 (prothioconazole) is prepared through 3
different routes from INT-1 and INT 2. These routes are described in detail
25 below:
In Route 1: Reacting compound 6 with ammonium thiocynate in ethylacetate to
obtain the compounds 1-(2-(1- chlorocyclopropyl)-3-(2-chlorophenyl)-
hydroxypropylhydrazinecarbothioamide (7A and 7B). The desired product (7A &
7B) formed isomers ((7(A): 2-(2-(1- chlorocyclopropyl)-3-(2 chlorophenyl)-2-
16
hydroxypropyl)thiosemicarbazide ) and (7(B) 1-(2-(1-chlorocyclopropyl)-3-(2-
chlorophenyl)-2-hydroxypropyl)thiosemicarbazide ) and recrystallized with
methanol to remove undesired isomer which gives lower yield.
In Route 2:
5 (i) Reacting compound 2-(1-chlorocyclopropyl)-2-[(2-
chlorophenyl)methyl]oxirane (INT-2) with 1, 2-4 triazole to obtain
compound 10. However 1, 2, 4- Triazole gives isomerization which
leads to formation of regio-isomer as impurity 2-(1-
chlorocyclopropyl)-1-(2-chlorophenyl)-3-(4H-1,2,4-triazol-4-yl)propan10 2-ol.
(ii) Reacting Compound 10 with sulfur and DMF at temperature 145-
150o
C to obtain compound 8.
In Route 3:
Reacting Compound 6 with glyoxylic acid and water-acetonitrile to obtain 2-(2-(2-
15 (1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl)hydrazono)acetic acid
(compound 11). Compound 11 was further treated with sodium thiocynate and
acetic acid to form crude product (compound 8). The crude product is subjected
to purification with n- heptane. Purity of the compound 8 obtained is more than
>98% as determined by Chromatography (HPLC).
20 In another embodiment, compound 8 obtained from route 3 is of high purity and
excellent yield. (86%).
In a specific embodiment, the present invention discloses a novel route for
synthesis of INT 1, INT 2, and the fungicidal compound, Prothioconazole, as
depicted in Fig. 1.
25 Examples
The examples below are given solely for the purpose of illustration and are not to
be construed as limitations of the present invention, as many variations thereof
are possible without departing from the spirit and scope of the invention.
Example 1: Step-1 to 3: General procedure for the synthesis of 1-(1-
17
Chlorocyclopropyl)-2-(2-chlorophenyl) ethanone (INT-1)
Synthesis of 2,4- dichlorobutanoylchloride (2): A solution of 𝛾-butyrolactone 1
(100.0 g, 1.16 mol) in excess of thionyl chloride was treated with 3.5% (w/w)
ZnCl2 for 10-22 hours. In the presence of catalyst (1,2 dibromoethane), the
5 excess thionyl chloride can increase the rate of conversion of butyrolactone to
2,4- dichlorobutanoylchloride. The excess of thionyl chloride is then removed
under vacuum to isolate the crude product (192.1 g) which is used as such in the
next reaction.
Example 2: Synthesis of 1-(2-chlorobenzene)-3,5-dichloropent-2-one (4)
10 To a suspension of magnesium turnings (21.1 g, 0.87 mol) in anhydrous diethyl
ether (250 mL), a catalytic amount of 1,2-dibromoethane was added. After 10
minutes, 2-Chlorobenzyl chloride (100.0 g, 0.62 mol, 1.3 eq.) in Et2O (250 mL)
was slowly added at room temperature under nitrogen atmosphere. During the
addition, the temperature was increased up to reflux. After the addition was
completed, the reaction mixture was stirred at 35-40o
15 C for an hour. In a separate
round bottom flask, to a solution of 2,4-dichlorobutanoyl chloride2 (81.4 g, 0.47
mol, 1.0 eq) THF (200 mL) was added drop wise at 20-25o
C. After the addition
was completed, the reaction mixture was stirred for an hour at the same
temperature. The progress of reaction was monitored using Thin Layer
20 Chromatography. The reaction mixture was treated with saturated aqueous
NH4Cl solution (200 mL) and extracted using ethyl acetate. The organic phase
was washed with brine, dried over anhydrous sodium sulfate and concentrated
under reduced pressure to afford 123.0 g of 1-(2-chlorobenzene),3,5-
dichloropent-2-one 4 (yield 89%).
25 Example 3. Synthesis of 1-(1-Chlorocyclopropyl)-2-(2-chlorophenyl)ethanone
(INT-1)
In 1 L three neck dry Round Bottom Flask (RBF), ethylene glycol (295.0 g, 4.7 mol,
1.27 eq.) and small pieces of sodium metal (13.80 g, 0.56 mol, 1.5 eq.) were
added with stirring until completion of the reaction at 20°C. The reaction mixture
18
was warmed to 80°C, to which, 1-(2-chlorobenzene)-3,5-dichloropent-2-one 4
(100.0 g, 0.37 mol, 1.0 eq.) was added dropwise. After completion of addition,
the reaction was continued for an hour. The reaction mixture was cooled to
room temperature and extracted twice with dichloromethane and the extract
5 was dried over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to afford 75.2 g of 1-(1-Chlorocyclopropyl)-2-(2-chlorophenyl)
ethanone (INT-1) (87% yield) as a pale-yellow transparent liquid.
1H NMR (400 MHz): δ (ppm) 7.1-7.4 (m, 4H), 4.2 (s, 2H), 1.2-1.7 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ (ppm) 18.0, 48.2, 49.0, 128.0, 128.5, 129.0, 129.4,
10 132.0, 134.5, 200.6.
Example 5: General procedure for the synthesis of compounds 5a-g
To a solution of 1-chlorocyclopropanecarboxylic acid (1.0 eq.) in hexane (10 Vol)
thionyl chloride (2.0 eq.) was added at 25-30o
C, and heated 40-45o
C. Then the
mixture was concentrated under reduced pressure. To that corresponding amine
15 or alcohol (1.2 to 2.0 eq.) was added and the stirring was continued for another
two-three hours to afford amides or esters respectively.
1-Chloro-N-methoxy-N-methylcyclopropane carboxamide (5a): light brown
liquid; 1H NMR (DMSO, 400 MHz) δ (ppm) 3.71 (s, 3H), 3.21 (s, 3H), 1.17-1.37 (m,
4H).
20 1-Chlorocyclopropanecarbonyl chloride (5b): colourless liquid; the compound
was confirmed by preparing following ester.
Methyl 1-chlorocyclopropanecarboxylate (5c): colourless liquid; 1H NMR (DMSO,
400 MHz) δ (ppm) 1.40-1.49 (m, 2H), 1.56-1.63 (m, 2H), 3.69 (s, 3H).
Ethyl 1-chlorocyclopropanecarboxylate (5d): colourless liquid; 1H NMR (DMSO,
25 400 MHz) δ (ppm) 4.13 (q, J = 7.2 Hz, 2H), 1.56-1.59 (m, 2H), 1.38-1.43 (m, 2H),
1.19 (t, J = 7.2 Hz, 3H).
1-Chloro-N-cyclohexylcyclopropanecarboxamide (5e): white solid; 1H NMR
(CDCl3, 400 MHz) δ (ppm) 6.69 (br. s, 1H), 3.67-3.75 (m, 1H), 1.87-1.91 (m, 2H),
1.56-1.72 (m, 5H), 1.29-1.40 (m, 3H), 1.16-1.24 (m, 4H).
19
1-Chloro-N,N-dimethylcyclopropanecarboxamide (5f): white solid; 1H NMR
(DMSO, 400 MHz) δ (ppm) 3.59 (s, 6H), 1.32-1.36 (m, 2H), 1.27-1.21 (m, 2H).
(1-Chlorocyclopropyl)(morpholino)methanone (5g): white solid; 1H NMR
(DMSO, 400 MHz) δ (ppm) 3.15 (br. s, 4H), 2.82 (br. s, 4H), 1.21-1.33 (m, 4H).
5 Step-3A: General procedure for the synthesis of 1-(1-Chlorocyclopropyl)-2-(2-
chlorophenyl)ethanone (INT-1) from 1-chloro-N-methoxy-Nmethylcyclopropane carboxamide (5a)
Stage (a): To a suspension of magnesium turnings (21.1 g, 0.87 mol) in anhydrous
Et2O (250 mL), a catalytic amount of 1,2-dibromoethane was added. After 10
10 minutes, 2-chlorobenzyl chloride (100.0 g, 0.62 mol, 1.3 eq.) in Et2O (250 mL) was
slowly added at room temperature (25-30o
C) under argon. During the addition,
the temperature was increased up to reflux. After the addition was completed,
the reaction mixture was stirred for an hour at 35-40o
C.
Stage (b): In a separate round bottom flask, to a solution of 1-chloro-N-methoxy15 N-methylcyclopropane carboxamide 5a (77.0 g, 0.47 mol, 1.0 eq.) in toluene (200
mL) was added the prepared Grignard reagent dropwise at 15-20o
C. After the
addition was completed, the reaction mixture was stirred for an hour at room
temperature. The progress of reaction was monitored by HPLC. After completion
of the reaction, the reaction mixture was quenched with dilute HCl solution. The
20 organic phase was washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to give 129.8 g (97% pure by
HPLC and yield 91.2%) of (1-Chlorocyclopropyl)-2-(2-chlorophenyl)ethanone INT1 as light brown liquid.
1H NMR (DMSO, 400 MHz): δ (ppm) 7.27-7.46 (m, 4H), 4.22 (s, 2H), 1.51-1.75 (m,
25 4H).
13C NMR (DMSO, 100 MHz) δ (ppm) 20.99, 43.03, 46.52, 126.88, 128.70, 129.80,
132.31, 132.97, 133.59, 201.32.
Comparative yield details and conditions for Step-3A using different derivatives
of 1-chlorocyclopropanecarboxylic acid used in this step:
20
Sr. No. Starting material
used in Step-3A
Temperature of Grignard
Reaction
Yield (%) of
Step-3A
1
N
O
Cl
O
5a
1. 15-20o
C for addition
2. 25-30o
C for reaction 91.2%
2
Cl
O
Cl
5b
1. -78o
C for addition
2. -78o
C for reaction 22.1%
3
O
O
Cl
5c
1. -78o
C for addition
2. -78o
C for reaction 41.3%
4
O
O
Cl
5d
1. -78o
C for addition
2. -78o
C for reaction 45.2%
5
N
H
O
Cl
5e
1. -20o
C for addition
2. 0
o
C for reaction 12.6%
6
N
O
Cl
5f
1. -20o
C for addition
2. -20o
C for reaction 19.4%
7
N
O
Cl
O
5g
1. -20o
C for addition
2. -20o
C for reaction 27.5%
Example 6: Step-4: General procedure for the synthesis of 2-(1-
Chlorocyclopropyl)-2-[(2-chlorophenyl)methyl]oxirane (INT-2)
In a three neck RBF, dimethyl sulphate (82.6 g, 0.65 mol, 1.5 eq.) was added
5 dropwise to a mixture of dimethyl sulphide (162.4 g, 2.62 mol, 6.0 eq.), 1-(1-
chlorocyclopropyl)-2-(2-chlorophenyl) ethanone INT-1 (100.0 g, 0.43 mol, 1.0
eq.) and water (8.64 g, 0.48 mol, 1.1 eq.) at 35-36o
C over the course of 20
minutes, while stirring. The mixture was then stirred at the same temperature
for further four hours. To that potassium hydroxide powder (73.36 g, 1.31 mol,
21
3.0 eq.) was added in portions and the stirring was continued for another three
to four hours. Then the reaction was quenched with water and extracted with
ethyl acetate. The organic phase was separated and washed with water, dried
over anhydrous sodium sulfate, filtered and concentrated to give 96.5 g of 2-(1-
5 chlorocyclopropyl)-2-[(2-chlorophenyl) methyl] oxirane INT-2 (97.4% pure by
HPLC and yield 91%) as light brown color liquid. Boiling point: 88-90o
C. The same
reaction was carried out using different bases like potassium hydroxide (yield
91%) or sodium hydroxide (yield 90%) or sodium methoxide (yield 90%) and all
cases gave the same consistent result.
1
10 H NMR (CDCl3, 400 MHz): δ (ppm) 7.17-7.28 (m, 4H), 3.64 (d, J = 16.2Hz, 1H),
3.35 (d, J = 16.0Hz, 1H), 2.65 (d, J = 8.0Hz, 1H), 2.38 (d, J = 8.0Hz, 1H), 0.83-1.1
(m, 4H).
13C NMR (CDCl3, 100 MHz) δ (ppm) 11.2, 40.1, 44.0, 52.6, 64.3, 130.0, 130.5,
131.2, 132.6, 134.0, 134.5.
15 Example 7: General procedure for the synthesis of 2-chloro-α-(1-
chlorocyclopropyl)-α-(hydrazinylmethyl)-benzenethanol hydrochloride (6)
To a stirred solution of 2-(1-Chlorocyclopropyl)-2-[(2-
chlorophenyl)methyl]oxirane INT-2 (100.0 g, 0.43 mol, 1.0 eq.) in methanol (500
mL) at 25-30o
C was added hydrazine hydrate (219.0 g, 4.3 mol, 10.0 eq.) and the
20 reaction mixture was heated under vigorous stirring at 65-70°C and kept at this
temperature for three to four hours. Then it was allowed to cool to 20o
C,
followed by the addition of water (8-10 volume). Obtained white solid was
filtered and the solid was taken in ethyl acetate (5 volume). The organic phase
was dried over anhydrous sodium sulfate and 1.5 equivalents of dry HCl gas was
25 introduced at cooling condition (with dry ice), stirred for 4-5 hours at room
temperature. The resulting solid was filtered, washed with ethyl acetate and
dried to give 109.0 g of 2-chloro-α-(1-chlorocyclopropyl)-α-(hydrazinylmethyl)-
benzeneethanol hydrochloride 6 (97.1% pure by HPLC and yield 85%) as off
white solid.
22
Example 8: Step-5B: General procedure of 1-(2-(1- chlorocyclopropyl)-3-(2-
chlorophenyl)-hydroxypropylhydrazinecarbothioamide (7A and 7B)
To a mixture of 2-(1-Chloro-cycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxy-propyl1-hydrazine hydrochloride 6 (100.0 g, 0.32 mol, 1.0 eq.) and ethyl acetate (500
5 mL), ammonium thiocyanate (24.4 g, 0.32 mol, 1.0 eq.) was added and the
mixture was stirred at 75o
C for another three hours. After completion of the
reaction, 300 mL of water was added and the phases were separated. The
organic phase was washed twice with saturated aqueous sodium chloride
solution and then with water, dried over anhydrous sodium sulfate and
10 concentrated under reduced pressure. Accordingly, the desired product 7A 1-[2-
(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropylhydrazinecarbothioam
ide was formed along with its isomer 7B. The mixture was isolated as Light
brown viscous liquid and the ratio of 7A and 7B is 76:21. The desired product
was recrystallized (using methanol as solvent to afford 63.2 g of 7A (95.6% pure
15 by HPLC and yield 59%)
Example 9: Step-5C: General procedure for the synthesis of 2-(1-chlorocydopropyl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazol-5-thiono-1-yl)-
propan-2-ol (8)
1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-
20 hydroxypropylhydrazinecarbothioamide 7A (100.0 g, 0.29 mol, 1.0 eq.) was
heated with formic acid (150 mL, 1.5 vol) in the presence of isobutyl formate
(300 mL, 3 vol) at 80o
C for five to six hours, then quenched with water and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to give 93.7g of 2-(1-
25 chloro-cydopropyl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazol-5-thiono-1-
yl)propan-2-ol 8 (97.6% pure by HPLC and 91% yield) as off white solid.
M.P.: 136-137 °C; 1H NMR (CDCl3): δ (ppm) 12.49 (brs, 1H); 7.86 (s, 1H); 7.52-7.56
(m, 1H); 7.34-7.39 (m, 1H); 7.16-7.25 (m, 2H); 4.79 (d, J = 18.5 Hz, 1H); 4.49 (d, J =
18.5 Hz, 1H); 4.23 (s, 1H); 3.61 (d, J = 17.5 Hz, 1H); 3.18 (d, J = 17.5 Hz, 1H); 0.90-
23
0.96 (m, 1H); 0.74-0.88 (m, 3H).
13C NMR (CDCl3, 100 MHz) δ (ppm) 8.5, 36.1, 49.8, 53.2, 74.9, 125.4, 126.3,
127.0, 127.5, 128.0, 134.0, 168.4.
Example 10: Step-6A: General procedure for the synthesis of, α-(1-
5 chlorocyclopropyl)-α-[(2-chlorophenyl)methyl-1,2,4-triazole-1-ethanol (10)
To a mixture of 2-(1-chlorocyclopropyl)-2-[(2-chlorophenyl)methyl]oxirane
(100.0 g, 0.43 mol, 1.0 eq.) in DMF (500 mL) was added 1,2,4-triazole (36.2 g,
0.52 mol, 1.2 eq.) and potassium tertiary butoxide (24.5g, 0.22 mol, 0.5 eq.) at
25-30o
C, then the temperature of the reaction was raised to 80o
C and the
10 reaction further maintain at the same temperature for three to four hours.
Reaction mixture was cooled, DMF was removed under vacuum and the reaction
mass was extracted with ethyl acetate. Organic phase was washed with water,
dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to give 116.8 g of α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl-1,
15 2,4-triazole-1-ethanol 10 as off white solid (yield 91%).
1H NMR (CDCl3, 400 MHz): δ (ppm) 8.25 (s, 1H), 7.94 (s, 1H), 6.98-7.53 (m, 4H),
4.96 (d, J = 16 Hz, 1H), 4.08 (s, 1H, 3.91 (d, J = 16 Hz, 1H), 3.73 (d, J = 16 Hz, 1H),
4.96 (d, J = 16 Hz, 1H), 0.30-0.98 (m, 4H).
13C NMR (CDCl3, 100 MHz) δ (ppm) 10.2, 40.1, 44.2, 52.6, 76.3, 126.0, 129.4,
20 130.0, 134.4, 135.2, 144.7, 151.8.
Example 11: Step-6B: General procedure for the synthesis of 2-(1-chlorocydopropyl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazol-5-thiono-1-
yl)propan-2-ol (8)
Mixture of 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(1,2,4-triazole-1-
25 yl)propan-2-ol 10 (100.0 g, 0.32 mol, 1.0 eq.), sulfur powder (82.0 g, 2.56 mol, 8.0
eq.) and N,N-dimethylformamide (200 mL) was heated while stirring for 48-50
hours at 145-150o
C. Then the reaction mixture was concentrated under reduced
pressure (0.2 mbar). The resulting crude product is recrystallized from
toluene. Obtained 70.6 g solid 2-(1-chloro-cydopropyl)-1-(2-chloro-phenyl)-3-
24
(4,5-dihydro-1,2,4-triazole-5-thiono-1-yl) propan-2-ol 8 (97.2% pure by HPLC and
yield 64%) was isolated as off white solid.
M.P.: 136-137 °C; 1H NMR (CDCl3, 400 MHz): δ (ppm) 12.49 (brs, 1H); 7.86 (s, 1H);
7.52-7.56 (m, 1H); 7.34-7.39 (m, 1H); 7.16-7.25 (m, 2H); 4.79 (d, J = 18.5 Hz, 1H);
5 4.49 (d, J = 18.5 Hz, 1H); 4.23 (s, 1H); 3.61 (d, J = 17.5 Hz, 1H); 3.18 (d, J = 17.5 Hz,
1H); 0.90-0.96 (m, 1H); 0.74-0.88 (m, 3H).
13C NMR (CDCl3, 100 MHz) δ (ppm) 8.5, 36.1, 49.8, 53.2, 74.9, 125.4, 126.3,
127.0, 127.5, 128.0, 134.0, 168.4.
Example 12: Step-7A: General procedure for the synthesis of 2-(2-(2-(1-
10 chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl)hydrazono)acetic acid
(11)
To a mixture of 2-chloro-α-(1-chlorocyclopropyl)-α-(hydrazinylmethyl)-benzene
ethanol hydrochloride 6 (100.0 g, 0.32 mol, 1.0 eq.) in water-acetonitrile (8:1,
880 mL) 50% aq., solution of glyoxylic acid (48.72 g, 0.24 mol, 0.8 eq.) was added
drop wise at 25-30o
15 C. Then the reaction mixture was stirred at the same
temperature for 2-3 h. After completion of reaction, the solid was filtered and
washed with water (200 mL). Then the solid was triturated with hexane to afford
104.0 g of 2-(2-(2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-
hydroxypropyl)hydrazono)acetic acid 11 as light yellow solid (yield 98%).
1
20 H NMR (CDCl3, 400 MHz): δ (ppm) 7.43-7.45 (m, 1H), 7.35-7.38 (m, 1H), 7.19-
7.22 (m, 2H), 7.12 (br. s, 1H), 6.75 (s, 1H), 4.75 (br. s, 1H), 3.85 (d, J = 14 Hz, 1H),
3.53 (d, J = 14 Hz, 1H), 3.45 (d, J = 14 Hz, 1H), 3.11 (d, J = 14 Hz, 1H), 1.12-1.17 (m,
1H), 0.85-0.94 (m, 1H).
Example 13: Step-7B: General procedure for the synthesis of 2-(1-chloro25 cydopropyl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazol-5-thiono-1-
yl)propan-2-ol (8)
A mixture of 2-(2-(2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-
hydroxypropyl)hydrazono) acetic acid 11 (50.0 g, 0.151 mol, 1.0 eq.), sodium
thiocyanate (24.48 g, 301.9 mol, 2.0 eq.) and acetic acid (200 mL) was stirred at
25
25-30o
C for 24 hours. Then the reaction mixture was poured in to water (500
mL). The obtained solid was filtered and washed with heptane to afford 45.2g of
2-(1-chloro-cydopropyl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazole-5-
thiono-1-yl) propan-2-ol 8 ( 99.79% pure by HPLC and yield 86%) was isolated as
5 off white solid.
M.P.: 136-137 °C; 1H NMR (CDCl3, 400 MHz): δ (ppm) 12.49 (brs, 1H); 7.86 (s, 1H);
7.52-7.56 (m, 1H); 7.34-7.39 (m, 1H); 7.16-7.25 (m, 2H); 4.79 (d, J = 18.5 Hz, 1H);
4.49 (d, J = 18.5 Hz, 1H); 4.23 (s, 1H); 3.61 (d, J = 17.5 Hz, 1H); 3.18 (d, J = 17.5 Hz,
1H); 0.90-0.96 (m, 1H); 0.74-0.88 (m, 3H).
13
10 C NMR (CDCl3, 100 MHz) δ (ppm) 8.5, 36.1, 49.8, 53.2, 74.9, 125.4, 126.3,
127.0, 127.5, 128.0, 134.0, 168.4.

I /WE CLAIM:
1. A process for the preparation of a benzyl ketone (INT 1) of formula I below:
5 Formula I
wherein said process comprises steps of:
i) reacting 2-chloro-benzyl chloride with magnesium turnings in the presence
of diethyl ether and at least one catalyst, at a temperature in the range of
25o
C to 35o
C to form (2-chlorobenzyl)magnesium chloride (Grignard
10 reagent) of formula
ii) reacting (2-chlorobenzyl)magnesium chloride obtained in step (i) with amides
or acid chlorides or esters of general formula
15 where, R is selected from the group consisting of NMe(OMe), Cl, OMe, OEt,
NH-Cyclohex, NMe2, and morpholine in the presence of 1
Chlorocyclopropanecarboxylicacid derivatives at a temperature range of78o
C to 30o
C in the presence of toluene under inert atmosphere to obtain
benzyl ketone (INT 1).
20 2. The process as claimed in claim 1, wherein the derivatives used in step (ii) is
selected from the group consisting of:
1-chloro-N-methoxy-N-methylcyclopropanecarboxamide (5a);
1-chlorocyclopropanecarbonyl chloride (5b);
methyl 1-chlorocyclopropanecarboxylate (5c);
Cl
O
Cl
INT-1
Cl
Mg
Cl
R
O
Cl
27
ethyl 1-chlorocyclopropanecarboxylate (5d);
1-chloro-N-cyclohexylcyclopropanecarboxamide (5e);
1-chloro-N,N-dimethylcyclopropanecarboxamide (5f); and
(1-chlorocyclopropyl)(morpholino)methanone (5g).
5 3. The process as claimed in claim 1, wherein the catalyst used in step (i) is
selected from the group consisting of 1,2 dibromo ethane, iodine, methyl iodide,
and ferric chloride.
4. The process as claimed in claim 1, wherein said derivatives used in step (ii) is
1-chloro-N-methoxy-N-methylcyclopropanecarboxamide 5(a) and wherein the
temperature is in the range of 15- 30o
10 C
5. The process as claimed in claim 2, wherein the derivatives 1-chloro-Nmethoxy-N-methylcyclopropanecarboxamide 5(a) and wherein the yield of INT 1
is in the range of 90-95%, more particularly 91.2%.
6. A process for the preparation of an oxirane (INT 2) of formula II:
15
Cl
Cl
INT-2
O
Formula II
comprising reacting dimethyl sulphate with an excess of dimethyl sulphide
thereby to form trimethylsulphonium methyl-sulphate and without prior
20 isolation, reacting the trimethylsulphonium methyl-sulphate with INT 1 of
claim 1 (1-(1-chlorocyclopropyl)-2-(2-chlorophenyl)ethanone) in the
presence of any of solid potassium hydroxide, sodium hydroxide, and
sodium methoxide as a base.
7. The process as claimed in claim 6, wherein the reaction of dimethyl sulphate
25 with dimethyl sulphide is carried out at the boiling point of dimethyl sulphide.
8. A process for the preparation of compound 8 of formula III below:
28
Formula III
comprising the steps:
i) reacting the compound (2-chloro-α-(1-chlorocyclopropyl)-α5 (hydrazinylmethyl)-benzeneethanol hydrochloride) with an
aqueous solution of glycolic acid at a temperature in the range of
25-30o
C to obtain 2-(2-(2-(1-chlorocyclopropyl)-3-(2-
chlorophenyl)-2-hydroxypropyl)hydrazono)acetic acid;
ii) isolating compound 2-(2-(2-(1-chlorocyclopropyl)-3-(2-
10 chlorophenyl)-2-hydroxypropyl)hydrazono)acetic acid obtained
from step (i) and reacting with sodium thiocyanate and acetic acid
at a temperature in the range of 25-30o
C to obtain compound of
formula III.
9. The process as claimed in claim 8, wherein said process has a product yield in
15 the range 82-86%
10. The process as claimed in claim 8, wherein the compound of formula III has
purity in the range of 98.2-99.8% as determined by HPLC.