U.S. patent application number 12/075227 was filed with the patent office on 2008-07-03 for process for the synthesis of 6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinoline-3-carbonitrile.
This patent application is currently assigned to Wyeth. Invention is credited to Michel Bernatchez, Sylvain Daigneault, Ronald Stanley Michalak.
Application Number | 20080161575 12/075227 |
Document ID | / |
Family ID | 34375310 |
Filed Date | 2008-07-03 |
United States Patent
Application |
20080161575 |
Kind Code |
A1 |
Daigneault; Sylvain ; et
al. |
July 3, 2008 |
Process for the synthesis of
6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinoline-3-carbonitrile
Abstract
The present invention provides a process for the preparation of
6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le comprising the steps and products disclosed within this
application.
Inventors: |
Daigneault; Sylvain;
(Laval-sur le-lac, CA) ; Michalak; Ronald Stanley;
(Congers, NY) ; Bernatchez; Michel; (Montreal,
CA) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
34375310 |
Appl. No.: |
12/075227 |
Filed: |
March 10, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10939008 |
Sep 10, 2004 |
7365203 |
|
|
12075227 |
|
|
|
|
60503106 |
Sep 15, 2003 |
|
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|
Current U.S.
Class: |
546/153 ;
546/171 |
Current CPC
Class: |
C07C 233/43 20130101;
C07C 233/25 20130101; C07C 255/30 20130101; C07D 215/54 20130101;
C07D 215/56 20130101 |
Class at
Publication: |
546/153 ;
546/171 |
International
Class: |
C07D 215/233 20060101
C07D215/233; C07D 215/18 20060101 C07D215/18 |
Claims
1. (canceled)
2. A compound consisting of
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline.
3. A compound consisting of
4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline.
4-15. (canceled)
16. A process for the preparation of
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline by heating
3-(4-Acetamido-3-ethoxyaniline)-2-cyano-propenoic acid ethyl
ester.
17. The process of claim 16 further comprising converting
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline to
6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le or a pharmaceutically acceptable salt form thereof.
Description
[0001] This application claims priority from copending provisional
application Ser. No. 60/503,106, filed Sep. 15, 2003, the entire
disclosure of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The two most frequently used synthetic methods for the
preparation of 3-cyano-4-quinolones or 3-carboalkyloxyquinolones
are intramolecular Friedel-Crafts reactions and electrocyclic ring
closures of N-(2-carboxyvinyl)-aniline derivatives. Friedel-Crafts
conditions work well for electron rich anilines, moderately for
unsubstituted anilines, and poorly or not at all for
electron-deficient anilines and are not useful for large scale
preparation of 3-cyano-4-quinolones especially utilizing electron
deficient anilines. The electron withdrawing groups of the aniline
reduce the nucleophilicity of the aromatic ring to the point that
side reactions compete with, if not dominate, the desired
intramolecular condensation.
[0003] Thermal conditions for electrocyclic ring closures of
N-(2-carboxyvinyl)-aniline derivatives typically require
temperatures in excess of 240.degree. C. In U.S. Pat. No. 6,002,008
the construction of 3-cyano-4-quinolones has been achieved by
electrocyclic ring closure reactions of N-(2-carboxyvinyl) aniline
derivatives by heating to 260.degree. C. in diphenyl ether. Thermal
decomposition of either the final product and/or the starting
material may compromise the purity of the final product as a result
of the high temperature reaction conditions. As a result, reactions
are often run at high dilution resulting in an inefficient
large-scale process due to low throughput.
[0004] The production of 3-cyano-4-quinolones by electrocyclic ring
closure suffers from all of the problems mentioned above. For
example, it is known that
7-ethoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile decomposes at
240.degree. C. while the minimum temperature required for
cyclization is 256.degree. C.
[0005] There is a need for a process which overcomes the problem of
thermal decomposition of intermediate compounds, including
6-amino-4-(3-chloro-4-fluoro-1-phenylamino)-7-ethoxy-quinoline-3-carbonit-
rile used to epidermal growth factor receptor (EGFR) inhibitors
useful in the treatment of cancer.
[0006] The following experimental details are set forth to aid in
an understanding of the invention, and are not intended, and should
not be construed to limit in any way the invention set forth in the
claims that follow thereafter.
BRIEF SUMMARY OF THE INVENTION
[0007] This invention relates to producing
6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le which comprises: [0008] (a) acylating 2-Amino-5-nitrophenol with
an acylating agent to obtain 2-Acetamido-5-nitrophenol; [0009] (b)
alkylating 2-Acetamido-5-nitrophenol of step (a) with an alkylating
agent in the presence of a base to obtain
4-Acetamide-3-ethoxynitrobenzene; [0010] (c) reacting
4-Acetamide-3-ethoxynitrobenzene of step (b) to obtain
4-Acetamido-3-ethoxy-aniline; [0011] (d) condensing
4-Acetamido-3-ethoxy-aniline of step (c) with
(ethoxymethylene)cyanoacetate to yield
3-(4-acetamido-3-ethoxyaniline)-2-cyano-propenoic acid ethyl ester;
[0012] (e) cyclizing
3-(4-Acetamido-3-ethoxyaniline)-2-cyano-propenoic acid ethyl ester
of step (d) to yield
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline; [0013] (f) reacting
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline of step (e) with a
chlorine-substituting reagent to obtain
4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline; [0014] (g)
hydrolyzing 4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline of step
(f) with acid to yield
6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carb-
onitrile; [0015] (h) optionally converting
6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le to a pharmaceutically acceptable salt form thereof.
[0016] Pharmaceutical acceptable salts can be formed from organic
and inorganic acids, for example, acetic, propionic, lactic,
citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,
malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,
sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known acceptable
aids when a compound of this invention contains a basic moiety.
Salts may also be formed from organic and inorganic bases, such as
alkali metal salts (for example, sodium, lithium, or potassium)
alkaline earth metal salts, ammonium salts, alkylammonium salts
containing 1-6 carbon atoms or dialkylammonium salts containing 1-6
carbon atoms in each alkyl group, and trialkylammonium salts
containing 1-6 carbon atoms in each alkyl group, when a compound of
this invention contains an acidic moiety.
[0017] In accordance with this invention there is provided the
following compounds and a process for the synthesis of
2-Acetamido-5-nitrophenol; 4-Acetamido-3-ethoxynitrobenzene,
3-(4-Acetamido-3-ethoxyaniline)-2-cyanopropenoic acid ethyl ester,
4-acetamido-3-ethoxy-aniline,
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline,
4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline, and
6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The process of the invention is shown in Scheme I:
##STR00001##
[0019] The acetylation of 2-Amino-5-nitrophenol 1 is performed by
adding an acylating agent at 60.degree. C. to a stirred suspension
of 2-Amino-5-nitrophenol and acetic acid to yield
2-Acetamide-5-nitrophenol 2.
[0020] The alkylation of 2-Acetamido-5-nitrophenol 2 is performed
by adding an alkylating reagent to yield
4-Acetamido-3-ethoxynitrobenzene 3.
[0021] 4-Acetamido-3-ethoxynitrobenzene 3 in tetrahydrofuran (10
parts) was reduced to 4-Acetamido-3-ethoxy-aniline 4 under
hydrogenation conditions (10% Pd/C wet, 50 psi, 2 hours). The
concentrate was condensed by dilution with toluene and reaction
with commercially available ethyl (ethoxymethylene) cyanoacetate at
reflux for 16 hours. After the reaction reached completion, the
mixture was cooled. The precipitated product was collected by
filtration, washed and dried to yield
3-(4-Acetamido-3-ethoxyaniline)-2-cyanopropenoic acid alkyl ester
5.
[0022] 3-(4-Acetamido-3-ethoxyaniline)-2-cyanopropenoic acid ethyl
ester 5 was cyclized in a solvent at a temperature of about
230-258.degree. C. (in a preferred embodiment the temperature was
250.degree. C.) to yield
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline 6.
[0023] 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline 6 was reacted
with a chlorine-substituting reagent to yield
4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline 7 followed by
condensation with 3-chloro-4-fluoroaniline optionally in the
presence of acid to yield
N-[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-acet-
amide 8.
[0024]
N-[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl-
]-acetamide 8 was hydrolyzed with acid to yield
6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le 9.
EXAMPLE 1
2-acetamido-5-nitrophenol
[0025] Acetic anhydride (398 g, 3.90 mol) was added to a stirred
suspension of 2-amino-5-nitro-phenol (400 g, 2.60 mol) and acetic
acid (1.60 L) at 62.5.degree. C. The reaction mixture was stirred
at 62.5.degree. C. for 1 hour, and then cooled to room temperature.
Water (2.00 L) was added over 20 minutes to the stirred reaction
mixture. After stirring for 1 hour, the solid was collected by
vacuum filtration and washed with water and heptane. Drying the
product in vacuo at 60.degree. C. yielded 486.7 g (96%, 99.5% by
HPLC) of N-(2-hydroxy-4-nitro-phenyl)-acetamide. .sup.1H NMR
(DMSO-d.sub.6) .delta. (ppm) 2.18 (s, 3H), 7.70 (m, 2H), 8.30 (d,
1H), 9.45 (s, 1H), 11.00 (s, 1H).
EXAMPLE 2
2-Acetamido-5-nitrophenol
[0026] A 5-L multi-necked flask equipped with a mechanical stirrer,
reflux condenser, nitrogen inlet, 500-mL addition funnel, heating
mantle, and a thermocouple attached to a temperature controller was
charged with 400 g 2-Amino-5-nitrophenol. The flask was than
charged with 1.6 L of acetic acid. The resulting mixture was
stirred and warmed to 60.+-.2.degree. C. to achieve a suspension.
While maintaining the temperature at 62.5.+-.2.5.degree. C. 398 g
of acetic anhydride was added over 1.5 hours and stirred for one
hour to 2-Acetamido-5-nitrophenol with less than 1% of
2-Amino-5-nitrophenol present. If necessary 37 mL of acetic acid
was added to reduce the concentration of 2-Amino-5-nitrophenol. The
reaction mixture was cooled to 20.+-.5.degree. C. and 2.00 L of
water was added over 20 minutes and the suspension was stirred for
one hour. Using vacuum filtration the suspension containing
2-Acetamido-5-nitrophenol was collected washed with water followed
by a heptane wash, and dried in a vacuum. Yield 486.7 g (96%),
strength 101.2%, mp>250.degree. C., .sup.1HNMR (DMSO d.sub.6)
.delta.1.42 (t, 3H), 2.20 (s, 3H), 4.25 (q, 2H), 7.78 (d, 1H), 7.78
(dd, 1H), 8.36 (d, 1H), 9.42 (s, 1H).
EXAMPLE 3
4-Acetamido-3-ethoxynitrobenzene
[0027] A 12-L, 4-necked flask equipped with a reflux condenser,
nitrogen inlet, thermocouple, addition funnel, and mechanical
stirrer was charged with 400 g 2-Acetamido-5-nitrophenol. The flask
was charged with 790 g potassium carbonate and 2.0 L of
dimethylformamide (DMF). The mixture was stirred and warmed to
60.+-.2.5.degree. C. 294 g of ethyl bromide or ethyl iodide was
added over 10 minutes to one hour while maintaining a 60.degree. C.
internal temperature. The reaction mixture was stirred for at least
one hour or until the mixture turned yellow and the concentration
of 2-Acetamido-5-nitrophenol was less than 1%, if needed additional
ethyl bromide or ethyl iodide was added to reduce the concentration
of 2-Acetamido-5-nitrophenol present. The mixture was cooled to
20.+-.5.degree. C. 4 L of water was added and while maintaining a
25.+-.5.degree. C. internal temperature. The suspension was stirred
for a minimum of 30 minutes and collected by vacuum filtration. The
product was washed and the pH monitored for a pH of <8. If the
pH was >8, the product was washed with 1.0 L portions of warm
water until the pH was <8. The resultant product was washed with
heptane and vacuum dried. Yield 98%, strength 98.6%, mp
164-165.degree. C.
EXAMPLE 4
3-(4-Acetamido-3-ethoxyaniline)-2-cyano-propenoic acid ethyl
ester
[0028] A 2-gallon Parr #2 hydrogenator was purged with nitrogen and
charged with 10% palladium on carbon (35 g, 50% wet) and
4-Acetamido-3-ethoxynitrobenzene (420 g, 1.87 mol). The closed
reactor was purged an additional 3 times with nitrogen and
tetrahydrofuran (THF, 4.2 L) was added from a pressure bomb. The
reactor was purged an additional 3 times with nitrogen and 3 times
with hydrogen and the reaction mixture was hydrogenated at 50 psi
at 28-30.degree. C. for 3 hours using an uptake meter. After
completion the reaction mixture was filtered and rinsed with THF
(300 mL). A 6 L multi-neck flask with a mechanical stirrer,
thermometer, still head for reduced pressure distillation,
condenser, and receiver was charged with the filtrate using a THF
rinse. The solution was concentrated to 840 mL. The filtrate was
stirred with toluene (5.5 L) and ethyl(ethoxymethylene)cyanoacetate
(475 g, 2.81 mol) and heated to reflux of 90.degree. C. with
stirring for 16 hours. The product was filtered and washed with
toluene and dried with a vacuum to yield
3-(4-Acetamido-3-ethoxyaniline)-2-cyanopropenoic ethyl ester as a
mixture of cis-trans isomers. Yield 534.0 g, 90.3%, .sup.1H NMR
(DMSO-d.sub.6) .delta.1.25 (m, 6H), 1.38 (t, 6H), 2.10 (s, 3H),
3.35 (s, 3H), 4.05-4.30 (m, 8H), 6.95 (t, 2H), 7.10 (s, 1H), 7.25
(s, 1H), 7.85 (d, 2H), 8.30 (d, 2H), 8.50 (d, 2H), 9.00 (s, 2H),
10.70 (d, 2H).
EXAMPLE 5
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline
[0029] A 22 L 4-necked flask equipped with a reflux condenser,
nitrogen inlet, two thermocouples attached to two independent
temperature controllers, and a mechanical stirrer was charged with
210 g of 3-(4-Acetamido-3-ethoxyaniline)-2-cyanopropenoic acid
ethyl ester. The flask was charged with 12.0 L of Dowtherm A. A
nitrogen flow was introduced over the reaction, venting through the
condenser. The mixture was stirred and warmed to 250.+-.5.degree.
C. while maintaining the temperature and monitoring the reaction by
high performance liquid chromatography (HPLC) to obtain >49%
(relative area) 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline. The
reaction mixture was cooled to room temperature. The solid was
collected by filtration and washed with toluene. In a 2-L 4-necked
flask, equipped with a water-cooled condenser, overhead stirring
apparatus and N.sub.2 blanket the solid and THF were combined. The
mixture was stirred and warmed to reflux and maintained for a
minimum of 30 minutes. The resultant mixture was cooled to room
temperature, collected by filtration, washed with THF and vacuum
dried to yield 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline.
Yield 42%, strength 95.2%, mp>250.degree. C., .sup.1H NMR
(DMSO-d.sub.6) .delta.1.42 (t, 3H), 2.15 (s, 3H), 4.21 (q, 2H),
7.08 (s, 1H), 8.60 (s, 1H), 9.17 (s, 1H), 12.50 (s, 1H)
EXAMPLE 6
4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline
[0030] A 2-L 4-necked flask with a water-cooled condenser, thermal
probe connected to a temperature controller, heating mantle,
nitrogen blanket, and overhead stirrer was charged with 80 g of
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline. The flask was
charged with 1.6 L of diethylene glycol dimethyl ether or dioxane
and stirred. The flask was charged with 96.0 mL of phosphorus
oxychloride and warmed to 100.+-.2.degree. C. and maintained for 45
minutes. HPLC was used to verify that <1% (relative area)
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline remained in the
reaction mixture. The mixture was cooled to 80.+-.5.degree. C. and
25 g celite was added. The reaction mixture was filtered and the
flask and celite were washed with 3.times.100 mL and 1.times.50 mL
diethylene glycol dimethyl ether.
[0031] The volume of the filtrate was reduced using a vacuum. The
concentrated filtrates were added to a stirred aqueous solution of
70 g of K.sub.2CO.sub.3 in water while maintaining a temperature of
<50.degree. C. The solid was collected by filtration and washed
with warm water and toluene and vacuum dried to yield
4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline (55.7 g). Yield 65%,
strength 82%, mp 250.degree. C., .sup.1H NMR
(DMSO-d.sub.6+CDCl.sub.3) .delta.1.45 (t, 3H), 2.20 (s, 3H), 4.30
(q, 2H), 7.10 (m, 1H), 7.15-7.40 (m, 3H), 8.50 (s, 1H), 8.85 (s,
1H), 9.20 (s, 1H), 9.60 (s, 1H)
EXAMPLE 7
N-[-4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinoline-6-yl]-ace-
tamide
[0032] A stirred mixture of
N-(4-chloro-3-cyano-7-ethoxy-6N-acetylquinoline (274.5 g, 0.947
mol), 3-chloro-4-fluoroaniline (180 g, 1.24 mol), methanesulfonic
acid, (5.5 g, 0.057 mol), and 2-propanol (6.7 L) was warmed to
reflux (84.degree. C.) for 6.5 hours. After stirring overnight at
room temperature, the mixture was warmed to 80.degree. C. Water
(3.2 L) containing concentrated hydrochloric acid (655 mL of 38%
aqueous HCl) was added. The reaction was kept at reflux for 5
hours. The reaction mixture was cooled to 0.degree. C.-10.degree.
C. for 1 hour. The yellow solid product is collected by vacuum
filtration and washed with 20% 2-propanol/water (700 mL) and water
(2.times.700 mL). Drying the product in vacuo at 60.degree. C. gave
344.8 g (91%, 99% by HPLC) of
6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le as a hydrochloride salt. .sup.1H NMR (DMSO-d.sub.6+D.sub.2O)
.delta.1.42 (t, 3H), 4.25 (q, 2H), 7.05 (m, 1H), 7.1 (s, 1H),
7.35-7.50 (m, 3H), 7.65 (dd, 1H), 8.65 (s, 1H).
EXAMPLE 8
6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitril-
e
[0033] Aqueous potassium carbonate (1.0 L of 10%, 0.725 mol) was
added over 30 minutes to 45 minutes to a stirred suspension of
4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-aminoquinoline (HCl
salt, 391 g, 1.00 mol), methanol (3.90 L), and water (0.90 L)
maintained at 65.degree. C. Water (1.0 L) was then added over 15
minutes. The reaction mixture is allowed to cool to room
temperature and stir overnight. The reaction mixture was cooled to
0.degree. C.-5.degree. C. for 30 minutes. The solid product was
collected by vacuum filtration. The solid was washed with water
(3.times.100 mL, 50.degree. C.-55.degree. C.). Drying the product
in vacuo at 60.degree. C. gave 344.7 (97%, 99.2% by HPLC) of
6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitri-
le. .sup.1H NMR (DMSO-d.sub.6) .delta.1.42 (t, 3H), 4.25 (q, 2H),
5.55 (broad s, 2H), 7.05 (m, 1H), 7.2-7.3 (m, 3H), 7.38 (t, 1H),
8.4 (s, 1H), 9.22 (broad s, 1H); .sup.13C NMR (DMSO-d.sub.6)
.delta.15.09, 64.72, 91.78, 101.46, 108.43, 117.14, 117.57, 117.85,
118.16, 120.33, 121.52, 122.72, 140.05, 145.28, 148.02, 152.31,
155.55.
[0034] For purposes of this invention an acylating agent is for
example acetic anhydride, halide, and acetyl chloride.
[0035] For purposes of this invention an alkylating agent includes
ethyl iodide, ethyl bromide or ethyl chloride in an inert solvent
such as N,N-dimethylformamide or DMSO, N,N-dimethylacetamide,
acetone, or any ketone.
[0036] For purposes of this invention a base includes alkali metal
hydroxides, alkali metal acetates, pyridine,
4-dimethylaminopyridine, sodium carbonate, inorganic carbonates and
potassium carbonate.
[0037] For purposes of this invention a reducing agent includes
iron and ammonium chloride, sodium dithionite in an aqueous medium,
and hydrogen assisted by metal catalysis with metals such as
palladium and platinum dispersed on carbon or another inert
support.
[0038] For purposes of this invention a solvent includes benzene,
toluene, acetonitrile, diphenyl ether, or tetrahydrofuran (THF). In
a preferred embodiment the solvent is a mixture of biphenyl and
diphenyl ether.
[0039] For purposes of this invention a chlorine-substituting
reagent includes phosphorous oxychloride and phosphorous
pentachloride neat or in an inert solvent such as THF, dioxane,
oxalyl chloride, thionyl chloride or 1,2-dimethoxyethane.
[0040] For purposes of this invention an acid includes hydrochloric
acid, sulfuric acid, methanesulfonic acid, alkanesulfonic acids in
general, p-toluenesulfonic acid, benzenesulfonic acid, mineral
acids as for example hydrochloric acid, or arylsulfonic acids in
general.
* * * * *