U.S. patent application number 15/214499 was filed with the patent office on 2017-01-26 for process for the synthesis of chlorzoxazone.
The applicant listed for this patent is Procos S.P.A.. Invention is credited to Alessandro Barozza, Luigi Bogogna, Lavinia Cicione, Paolo Paissoni, Jacopo Roletto.
Application Number | 20170022172 15/214499 |
Document ID | / |
Family ID | 54364513 |
Filed Date | 2017-01-26 |
United States Patent
Application |
20170022172 |
Kind Code |
A1 |
Bogogna; Luigi ; et
al. |
January 26, 2017 |
PROCESS FOR THE SYNTHESIS OF CHLORZOXAZONE
Abstract
Disclosed is a process for the synthesis of chlorzoxazone (1)
from 4-chloro-2-aminophenol and ethyl chloroformate in the presence
of a base. ##STR00001## The process is particularly advantageous
because it uses ethyl chloroformate instead of triphosgene, a
highly dangerous reagent that releases phosgene and must be handled
with extremely strict procedures to guarantee the safety of
operators in industrial facilities. Ethyl chloroformate allows the
possibility of working with a number of solvents, including water.
The yield and purity of the product obtained are very high.
Inventors: |
Bogogna; Luigi; (Cameri,
IT) ; Cicione; Lavinia; (Novara, IT) ;
Barozza; Alessandro; (Nosate, IT) ; Roletto;
Jacopo; (Torino, IT) ; Paissoni; Paolo;
(Druento, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Procos S.P.A. |
Cameri |
|
IT |
|
|
Family ID: |
54364513 |
Appl. No.: |
15/214499 |
Filed: |
July 20, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 263/58
20130101 |
International
Class: |
C07D 263/58 20060101
C07D263/58 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 23, 2015 |
IT |
102015000037594 |
Claims
1. A process for the preparation of chlorzoxazone (1) wherein
4-chloro-2-aminophenol is reacted with ethyl chloroformate in the
presence of a solvent and a base, according to the following
scheme: ##STR00010##
2. A process according to claim 1 wherein the solvent is selected
from acetonitrile, N,N-dimethylformamide, dichloromethane, toluene,
acetone, ethyl acetate or water.
3. A process according to claim 1 wherein the base is selected from
potassium carbonate, potassium bicarbonate, sodium carbonate and
sodium bicarbonate.
4. A process according to claim 1 wherein the molar ratio of
4-chloro-2-aminophenol to ethyl chloroformate ranges from 0.9 to
1.5
5. A process according to claim 1 wherein the reaction is carried
out at a temperature ranging from 0.degree. C. to 80.degree. C. or
the reflux temperature in the case of low-boiling solvents.
6. A process according to claim 1, wherein the solvent is selected
from ethyl acetate, acetonitrile, N,N-dimethylformamide or
water.
7. A process according to claim 1, wherein the base is potassium
carbonate.
8. A process according to claim 1, wherein the molar ratio of
4-chloro-2-aminophenol to ethyl chloroformate ranges from 1.2 to
1.4.
9. A process according to claim 1, wherein the reaction is carried
out at a temperature of 55-60.degree. C.
Description
[0001] This application claims priority to and the benefit of
Italian Patent Application No. 102015000037594 filed on Jul. 23,
2015, incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Chlorzoxazone, 5-chlorobenzo[d]oxazol-2(3H)-one, is a muscle
relaxant which acts at central level and is used in the treatment
of muscle spasms and the resulting pain. Chlorzoxazone acts on the
spinal cord, by depressing/suppressing the reflexes.
[0003] A number of examples of synthesis of chlorzoxazone (1) from
4-chloro-2-aminophenol, into which an acyl group, usually from urea
or phosgene, is inserted, are described in the literature. Cases in
which the carbonyl group inserted is directly gaseous CO are also
reported.
[0004] A representative example of the use of urea for the
synthesis of chlorzoxazone (1) is reported in U.S. Pat. No.
3,812,138 (DE2131366), which discloses the formation of
dibenzothiazolones from various aminophenols/aminothiols in the
presence of urea and mineral acids according to the following
synthesis scheme:
##STR00002##
[0005] Specifically, chlorzoxazone (1) is synthesised by loading
concentrated HCl, 4-chloro-2-aminophenol and urea into an autoclave
and heating them in an inert atmosphere at 125.degree. C. After
cooling to room temperature, the crystalline paste that
precipitates is suspended in 1500 parts of water, the pH of the
suspension is adjusted to 5-6, and the paste is heated at
100.degree. C. for an hour. After cooling, the residue is filtered
and washed under vacuum to obtain chlorzoxazone (1) with a yield of
91%.
[0006] The patent does not report the degree of purity of the
product obtained and, despite the high yield of the process, this
synthesis is not particularly economical in terms of energy because
very high temperatures are used. Moreover, the required work-up
considerably increases the volumes of work, making it inefficient
on an industrial scale.
[0007] CN1560040 and CN103360336 also report the synthesis of
chlorzoxazone (1) by reacting 4-chloro-2-aminophenol with urea at
high temperatures in the presence of mineral acids (HCl or
H.sub.2SO.sub.4).
[0008] CN1560040 also discloses the synthesis of chlorzoxazone
using phosgene
##STR00003##
[0009] The same document also describes the synthesis of
chlorzoxazone (1) from the nitro derivative by reacting it with
gaseous CO, which leads to the formation of cyclic carbamate
##STR00004##
[0010] Another synthesis method involves cyclisation of
5-chloro-salicylamide by the action of 13% NaOH.
##STR00005##
[0011] An alternative process using phosgene is reported in U.S.
Pat. No. 3,369,022. The cyclisation of 4-chloro-2-aminophenol is
described in procedure no. 2, according to the following synthesis
scheme:
##STR00006##
[0012] In particular, a solution of phosgene in ethyl acetate is
dripped into a suspension of 4-chloro-2-aminophenol and sodium
acetate in ethyl acetate. The reaction mixture is heated to reflux
and cooled, then washed with water containing 5% hydrochloric acid.
After a distillation under vacuum and a further crystallisation,
the product is obtained.
[0013] The procedure does not provide any data relating to the
yield or purity of the chlorzoxazone (1) obtained, but even if they
were excellent, the process presents the significant drawback of
the manageability of phosgene, a particularly reactive, toxic
reagent which requires special precautions for both use and
disposal.
[0014] Another example of synthesis of chlorzoxazone (1) involving
the use of phosgene is reported in EP0477819. The procedure
described therein also appears unsatisfactory in terms of
yields.
[0015] Alternative methods of synthesising chlorzoxazone are
described in U.S. Pat. No. 2,895,877. Starting with
2-amino-5-chlorobenzoxazole or N-(5-chloro-2-hydroxyphenyl)urea at
reflux in 1N HCl a solid precipitates which, after a basic work-up
and an acid work-up, is crystallised from a suitable solvent.
[0016] An alternative synthesis method not requiring the use of
urea or phosgene is described in JP4834875, wherein a mixture of
4-chloro-2-nitrophenol, benzene, RhCl.sub.3 and V.sub.2O.sub.5 is
heated in an autoclave with CO.
##STR00007##
[0017] Also in JP58225072, chlorzoxazone (1) is obtained by heating
a suitable nitrophenol with CO in hydrated organic solvent (e.g.
THF) in the presence of a base (e.g. triethylamine) and
selenium.
[0018] SK278412 describes a process wherein 4-chloro-2-nitrophenol
is carbonylated with CO at high temperatures in the presence of
catalytic systems such as S, COS, H.sub.2S or CS, bases (alkoxides,
alkaline metal oxides, etc.) and vanadium derivatives
(V.sub.2O.sub.5, V.sub.2S.sub.5, NH.sub.3VO.sub.3).
[0019] EP0087347 discloses (Example 7) the synthesis of
chlorzoxazone (1) obtained directly from the nitro derivative in
the presence of pyridine and of a catalyst based on palladium and
molybdenum in a CO atmosphere (200 bars) at 200.degree. C. Cyclic
carbamate is then isolated by cooling, filtration of the catalyst
and recrystallisation of the product from water.
[0020] The use of CO is problematic; said gas is highly poisonous,
and insidious because it is odourless, colourless and tasteless.
Its extremely hazardous nature requires particular precautions
which make its industrial use extremely complicated.
[0021] RO75779 discloses the synthesis of chlorzoxazone (1) from
5-Cl-salicylamide; in particular, the desired product is obtained
by treating the amide in water, NaOH and butanol with 13% NaOCl at
35.degree. C.
##STR00008##
[0022] On the basis of the information set out above, there is
clearly a need to find a process for synthesising chlorzoxazone (1)
that is easier to manage industrially, safer, by avoiding the use
of reagents which are extremely hazardous to humans and the
environment, and more economical.
DESCRIPTION OF THE INVENTION
[0023] An advantageous process for the preparation of chlorzoxazone
(1) has been found wherein 4-chloro-2-aminophenol is surprisingly
closed with cyclic urethane due to ethyl chloroformate in the
presence of a base, according to the following scheme:
##STR00009##
[0024] The process takes place by degrees, without isolation of
intermediate reaction products.
[0025] The process therefore comprises:
[0026] 1) acylation of 4-chloro-2-aminophenol (cyclisation of the
various acylation products);
[0027] 2) isolation of chlorzoxazone (1) from the reaction mixture
by simple filtration of the reaction solvent.
[0028] The process of the invention typically involves the
synthesis of chlorzoxazone (1) by acylation of
4-chloro-2-aminophenol with ethyl chloroformate in an organic
solvent selected from acetonitrile, N,N-dimethylformamide,
dichloromethane, toluene, acetone and ethyl acetate, or in water in
the presence of an inorganic base, preferably potassium carbonate,
potassium bicarbonate, sodium carbonate or sodium bicarbonate.
[0029] The order in which the various solvents, raw materials and
base are added can differ from that reported below.
[0030] Chlorzoxazone (1) obtained is isolated directly from the
reaction mixture by simple filtration. The quality of the
synthesised product exceeds 98%.
[0031] According to a preferred embodiment of the invention, the
process is performed as follows:
[0032] 1 mole of 4-chloro-2-aminophenol is reacted with 0.9-1.5
moles of ethyl chloroformate, preferably 1.2-1.4 moles, in the
presence of an inorganic base, preferably potassium carbonate, in
quantities ranging from 1.0 to 4.0 moles, preferably from 2.0 to
3.0 mole equivalents. The reaction is performed in organic solvent
or mixtures of solvents selected from acetonitrile,
N,N-dimethylformamide, dichloromethane, toluene, acetone and ethyl
acetate or in water, preferably in ethyl acetate, acetonitrile,
N,N-dimethylformamide and water, in the temperature range between
0.degree. C. (addition temperature) and 80.degree. C. or reflux
temperature in the case of low-boiling solvents, preferably at the
temperature of 55-60.degree. C. 4-15 volumes of solvent are used,
preferably 5-7 volumes relative to the quantity of
4-chloro-2-aminophenol. The reaction is monitored by UPLC analysis
using an ACQUITY UPLC.RTM. BEH C18 column, 17 .mu.m, 2.1.times.50
mm, and water/acetonitrile/0.1% formic acid as eluent phase. After
completion of the reaction, the reaction mixture containing
chlorzoxazone (1) is cooled to the temperature of 0-25.degree. C.,
preferably 0-10.degree. C., and filtered. The solid is re-washed
with water and dried under vacuum at the temperature of
30-90.degree. C., preferably 60-70.degree. C., to obtain
chlorzoxazone with a purity exceeding 98%. The resulting solid can
be further purified if necessary by recrystallisation from ethyl
acetate, ethanol or other known solvents.
[0033] The process of the invention is particularly advantageous in
that ethyl chloroformate is cheap and readily available, is not
classified as a toxic gas, unlike phosgene and CO, does not need
strict anhydrous conditions, which means that the reaction can take
place in water, and does not need high reaction temperatures as
with the use of urea.
[0034] Moreover, chlorzoxazone (1) is obtained directly from the
reaction mixture by simple filtration of the suspension at the end
of the reaction with very high yields and quality, thus
considerably simplifying the work-up stages described in the
literature.
[0035] The invention is illustrated in detail in the following
examples.
Example 1
[0036] Ethyl chloroformate (9.8 g, 90.5 mmol) is dripped into a
suspension of potassium carbonate (27.9 g, 201.8 mol) and
4-chloro-2-aminophenol (10.0 g, 69.6 mmol) in ethyl acetate (70
mL), heated to 60.degree. C., in 4 hours. After completion of the
reaction, the mixture is cooled at 5.degree. C. for 1.5 hours, and
the reaction mixture is filtered and re-washed with ethyl acetate
(15 mL). The crude product is reduced to a pulp in water for 1.5
hours, filtered under vacuum and washed with water (10 mL);
chlorzoxazone (1) (11.1 g), with a purity exceeding 98%, is
obtained. Molar yield from 4-chloro-2-aminophenol to chlorzoxazone:
94%.
Example 2
[0037] Ethyl chloroformate (2.9 g, 26.3 mmol) is dripped into a
solution of 4-chloro-2-aminophenol (3.0 g, 20.9 mmol) and
triethylamine (2.7 g, 26.3 mmol) in acetonitrile (20.9 mL), cooled
to 0.degree. C. The mixture is left under stirring at 0.degree. C.
for one hour, and potassium carbonate (8.4 g, 60.8 mmol) is then
added. The resulting mixture is left under stirring at 60.degree.
C. for 18 h. After completion of the reaction, the mixture is
cooled at 5.degree. C. for 1.5 hours, and the reaction mixture is
filtered and re-washed with acetonitrile (5 mL). The crude product
is reduced to a pulp in water for 1.5 hours, filtered under vacuum
and washed with water (10 mL); chlorzoxazone (1), with a purity
exceeding 96%, is obtained. Molar yield from 4-chloro-2-aminophenol
to chlorzoxazone: 92%.
Example 3
[0038] Ethyl chloroformate (1.96 g, 18.1 mmol) is dripped into a
suspension of sodium bicarbonate (5.8 g, 69.0 mmol) and
4-chloro-2-aminophenol (2.0 g, 13.9 mmol) in water (11 ml) at
0.degree. C. The mixture is left to stand at room temperature for
about half an hour, after which potassium carbonate is added and
the reaction mixture is heated to 55-60.degree. C. The reaction is
finished after 2 hours. The reaction mixture is filtered and
re-washed with water (10 mL) to obtain chlorzoxazone (1) (2.3 g,
13.6 mol) with a purity exceeding 95%. Molar yield from
4-chloro-2-aminophenol to chlorzoxazone: 98%.
[0039] UPLC-MS [M-H].sup.-=168 m/z
[0040] .sup.1H-NMR (in DMSO) (chemical shifts expressed in ppm
relative to the TMS signal): 11.82 (1H, s), 7.31 (1H, d), 7.15 (1H,
dd), 7.13-7.11 (1H, m). .sup.13C-NMR: 154.7, 142.6, 132.2, 128.2,
121.9, 111.2, 110.3.
* * * * *