U.S. patent application number 15/480565 was filed with the patent office on 2017-10-12 for process for the preparation of toltrazuril and an intermediate useful for its preparation.
The applicant listed for this patent is ERREGIERRE S.p.A.. Invention is credited to Matteo Bonaldi, Daniele De Zani, Massimo Ferrari.
Application Number | 20170291880 15/480565 |
Document ID | / |
Family ID | 56555547 |
Filed Date | 2017-10-12 |
United States Patent
Application |
20170291880 |
Kind Code |
A1 |
Ferrari; Massimo ; et
al. |
October 12, 2017 |
PROCESS FOR THE PREPARATION OF TOLTRAZURIL AND AN INTERMEDIATE
USEFUL FOR ITS PREPARATION
Abstract
Disclosed is a process for the preparation of toltrazuril of
formula (I) via the intermediate
N-methyl-N'-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]
imidodicarbonic diamide of formula (III) ##STR00001## wherein
intermediate (III) is obtained via a novel intermediate without the
use of potentially hazardous reagents or potentially unstable
intermediates.
Inventors: |
Ferrari; Massimo; (Cenate
Sotto, IT) ; De Zani; Daniele; (Roncello, IT)
; Bonaldi; Matteo; (Sorisole, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ERREGIERRE S.p.A. |
San Paolo D'Argon |
|
IT |
|
|
Family ID: |
56555547 |
Appl. No.: |
15/480565 |
Filed: |
April 6, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 319/20 20130101;
C07C 271/66 20130101; C07C 323/20 20130101; C07C 275/60 20130101;
C07C 319/20 20130101; C07D 251/30 20130101 |
International
Class: |
C07D 251/30 20060101
C07D251/30; C07C 271/66 20060101 C07C271/66 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 11, 2016 |
IT |
102016000037106 |
Claims
1. A process for the preparation of toltrazuril of formula (I)
##STR00011## which comprises: a) reacting
(methylaminocarbonyl)carbamic acid phenyl ester of formula (VII)
##STR00012## with
3-methyl-4[4-(trifluoromethylthio)phenoxy]henzenamine of formula
(IV) ##STR00013## to give the compound of formula (III)
##STR00014## and b) cyclizing the compound of formula (III) to give
toltrazuril.
2. The process of claim 1 wherein the reaction between (IV) and
(VII) is carried out at a temperature ranging from 60.degree. C. to
80.degree. C. in an organic solvent selected from
N,N-dimethylformamide, N,N-dimethylacetamide and ethyl acetate, for
a time ranging from 6 to 18 hours.
3. The process of claim 1, wherein the compound of formula (VII) is
obtained reacting phenyl chloroformate with N-methylurea.
4. The process of claim 3, wherein the reaction between phenyl
chloroformate and N-methylurea is carried out in a solvent selected
from methylene chloride, ethyl acetate, acetone,
N,N-dimethylformamide and toluene in the presence of a base
selected from triethylamine and pyridine, wherein said reaction is
performed at a temperature ranging from 40.degree. C. to 60.degree.
C.
5. The compound of formula (VII) ##STR00015##
Description
[0001] This U.S. Non-Provisional Application claims priority to and
the benefit from Italian Patent Application No. 102016000037106
filed on Apr. 11, 2016, the content of which is incorporated herein
by reference in its entirety.
[0002] The invention relates to a process for the preparation of
toltrazuril and an intermediate for its preparation.
BACKGROUND TO THE INVENTION
[0003] Toltrazuril, (1-methyl-3-[3
-methyl-4-[4-(trifluoromethyl)thio)phenoxy]-phenyl]-1,3,5-triazin-2,4,6(1-
H,3H,5H)-trione) of formula (I), is an agent widely used in the
veterinary field for the prevention and treatment of coccidiosis,
particularly in poultry and pigs.
##STR00002##
[0004] The preparation of toltrazuril is reported in U.S. Pat. No.
3,966,725 and U.S. Pat. No. 4,219,552, which describe a general
process for the preparation of various
1-(4-phenoxyphenyl)-1,3,5-triazin-2,4,6 1H,3H,5H)-triones. In the
case of toltrazuril, the process involves reacting 1-[3-methyl-4-[4
(trifluoromethylthio)phenoxy]phenyl]-3-methylurea of formula (II)
with chlorocarbonyl isocyanate, as reported in Scheme 1.
##STR00003##
[0005] U.S. Pat. No. 4,874,860 and DE 4239000 disclose the
preparation of toltrazuril by cyclisation of
N-methyl-N'-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]-phenyl]imidodi-
carbonic diamide of formula (III), commonly known as biuret
toltrazuril intermediate, with diethyl carbonate in the presence of
sodium methylate, as reported in Scheme 2.
##STR00004##
[0006] The biuret intermediate (III) is obtained in turn by
reacting the aniline intermediate
3-methyl-4-[4-(trifluoromethylthio)phenoxy]benzenamine (IV) with
phosgene to give the corresponding isocyanate (V), which is then
reacted with N-methylurea, as reported in Scheme 3.
##STR00005##
[0007] CN 101265236 discloses the reaction of isocyanate (V) with
intermediate (IV) and triphosgene instead of phosgene, while
CN102108067 describes the reaction between intermediate (IV) and
BOC-anhydride/DMAP.
[0008] CN 101108831 describes the preparation of toltrazuril
wherein the ureide intermediate (II) is obtained by treating
aniline (IV) with triphosgene to give isocyanate (V), which is then
reacted with methylamine, as reported in Scheme 4.
##STR00006##
[0009] CN 102731351 discloses the reaction of aniline (IV) with
KCNO giving urea (VI), which is converted to biuret (III) by
reaction with methylaminoformyl chloride, as depicted in Scheme
5.
##STR00007##
[0010] The synthesis routes of toltrazuril via intermediate (III)
reported so far therefore involve the use of potentially hazardous
reagents like phosgene and triphosgene and/or a step involving
unstable intermediates like isocyanates.
DESCRIPTION OF THE INVENTION
[0011] The object of the present invention is a process for the
preparation of toltrazuril which comprises: [0012] a) reaction of
(methylaminocarbonyl)carbamic acid phenyl ester of formula (VII)
with 3-methyl-4-[4-(trifluoromethylthio)phenoxy]benzenamine of
formula (IV) to give
N-methyl-N'-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-im-
idodicarbonic diamide of formula (III), as depicted in Scheme 6
below
[0012] ##STR00008## [0013] b) cyclisation of compound (III) to give
toltrazuril.
[0014] (Methylaminocarbonyl)carbamic acid phenyl ester (VII) is a
novel compound that is a further object of the invention. Said
compound can be obtained by reacting phenyl chloroformate of
formula (VIII) with N-methylurea, as reported in Scheme 7.
##STR00009##
DETAILED DESCRIPTION OF THE INVENTION
[0015] The reaction between aniline (IV) and
(methylaminocarbonyl)carbamic acid phenyl ester (VII) is carried
out using equimolar amounts of the reagents or a slight molar
excess (5-20%), preferably 5-10%, of (VII), at a temperature
ranging from 20.degree. C. to 90.degree. C., preferably from
60.degree. C. to 80.degree. C. The reaction is carried out in an
organic solvent selected from N,N-dimethylformamide,
N,N-dimethylacetamide and ethyl acetate, preferably
N,N-dimethylacetamide, for a time ranging from 6 to 18 hours,
preferably for 12 hours.
[0016] The phenylcarbamic intermediate (VII) is obtained by
reacting phenyl chloroformate (VIII) with N-methylurea in a solvent
selected from methylene chloride, ethyl acetate, acetone,
N,N-dimethylformamide and toluene, preferably toluene, in the
presence of a base selected from triethylamine and pyridine,
preferably pyridine. The reaction is conducted at a temperature
ranging from 40.degree. C. to 60.degree. C., preferably from
50.degree. C. to 60.degree. C.
[0017] 3-Methyl-4-[4-(trifluoromethylthio)phenoxy]benzenamine (IV)
is a known compound, which can be obtained by condensation between
4-(trifluoromethylthio)-phenol (IX) and 2-chloro-5-nitrotoluene (X)
in the presence of a base, followed by reduction of the resulting
nitro derivative (XI) with hydrogen and palladium-on-carbon
catalysis, as disclosed, for example, in U.S. Pat. No. 4,219,552
and summarised in Scheme 8.
##STR00010##
[0018] The biuret intermediate (III) can be converted to
toltrazuril by known procedures, for example by reaction with
diethyl carbonate in the presence of a base, as described in U.S.
Pat. No. 4,874,860.
[0019] The process according to the invention produces biuret
intermediate (III) with no need to use hazardous reagents such as
those described in the literature to date for its preparation, and
also avoids the step involving unstable intermediates considered
potentially hazardous, such as isocyanates. The invention will now
be illustrated by the following examples.
EXAMPLE 1
Preparation of [(methylamino)carbonyl]carbamic acid phenyl
ester
[0020] 20.5 Kg of N-methylurea (276.7 moles), 61.5 Kg of toluene
and 26.3 Kg of pyridine (332.5 moles) are loaded into a reactor.
The suspension is heated to 40-60.degree. C. and, maintaining said
temperature by cooling, 47.6 Kg of phenyl chloroformate (304.25
moles) is poured into it. The reaction is maintained at
50-60.degree. C. for one hour, after which 51.3 Kg of methanol is
added. The suspension is cooled to 0-10.degree. C., after which the
solid is recovered by filtration, washed with 30.8 Kg of methanol,
and dried at 60-70.degree. C. 45.1 Kg of
[(methylamino)carbonyl]carbamic acid phenyl ester (232.4 moles) is
obtained. HPLC purity=99%. Yield: 84%.
EXAMPLE 2
Preparation of
N-methyl-N'-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]imidodic-
arbonic diamide
[0021] 64.9 Kg of
3-methyl-4[4-[(trifluoromethylthio)]phenoxy]benzenamine (216.82
moles), 64.9 Kg of N,N-dimethylacetamide and 45.1 Kg of
[(methylamino)carbonyl]carbamic acid phenyl ester (232.2 moles) are
loaded into a reactor. The mass is heated at 60-80.degree. C. for
12 hours, after which 130 Kg of toluene, 130 Kg of water and 31.8
Kg of sodium hydrate (in 30% w/w aqueous solution) are added. The
lower aqueous phase is separated and eliminated, and 64.9 Kg of
distilled water is added to the organic phase. The mixture is
cooled to 30-45.degree. C. (crystallisation takes place), then
cooled to 0-5.degree. C. and filtered washing first with 64.9 Kg of
toluene and then with 64.9 Kg of distilled water. The resulting
product is dried at 60-70.degree. C. 74.5 Kg of
N-methyl-N'-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-imidodi-
carbonic diamide is obtained. HPLC purity=99%. Yield 86%.
* * * * *