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Патент USA US2128512

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2,128,512
Patented Aug. 30, 1938
UNITED STATES PATENT OFFICE
2,128,512
FREE METHAANE-SULPHONIG ACIDS 0F PY
RAZOLONEAMINES AND PROCESS OF PRE
PARING VTHEM
Max Bockmiihl and Leonhard Stein, Frankfort
on-the-Main-Hochst, Germany, assignors to
Winthrop Chemical Company, Inc., New York,
N. Y., a corporation of New York
No Drawing. Application January 8, 1935, Serial
No. 924. In Germany January 13, 1934
8 Claims. (Cl. 260-310)
sulphonic acid, 1-cyclohexyl-2.3-dimethyl-4
Our present invention relates to free methane
sulphonic acids of pyrazoloneamines and to a methylamino-5-pyrazolone- 4 -methanesu1phonic
process of preparing them.
I
It is known that the omega-alkylsulphonic
acids of aromatic amines are produced by caus
ing an aldehyde and sulphurous acid to act upon
an aromatic amine.
The same acids have been
acid,
1 - (4 - methylcyclohexyl) -2.3-dimethyl-4
methylamino-5-pyrazolone- 4 -methanesulphonic
acid, 1-para-tolyl-2.3-dimethyl-4-methylamino
5~pyrazolone-4-methanesulphonic acid, l-phen
yl-2-cyclohexyl-3-methyl-4-methylamino- 5 -py -
produced by acidifying the alkali metal salts of
razolone-4-methanesulphonic acid, 1-phenyl-2
omega-aminomethanesulphonic acids, obtained
by condensing aromatic amines with aldehydes
?-pyrazolone-4-methanesulphonic acid, l-phen
and alkali bisulphite. Though these acids are
highly liable to decomposition they may be iso
(4-methylcyclohexy1) -3-methyl-4~methylamino -
lated by taking advantage of their insolubility
methanesulphonic acid, 1-phenyl-2.3-dimethyl
4-phenylamino-5-pyrazolone-4-methanesulphon
or sparing solubility in water.
ic acid, 1-phenyl-2.3-dimethyl-4-para-to1yI-5-py
The application
of the above reactions to the amines of the py
razolone-4-methanesulphonic acid, 1-pheny1-2.3
razolone series has, hitherto, been unsuccessful,
dimethyl-4-cyclohexyl-5-pyrazolone-4-methane -
since the omega-aminoalkylsulphonic acids of
this series are extremely soluble in water and
no method has become known for separating the
free acids from aqueous solution; moreover, the
sulphonic
acid,
1-phenyl-2.3-dimethyl-4~(4
methyl-cyclohexyl) -5-pyrazolone-4-methanesul -
phonic acid, 1-phenyl-2.3-dimethyl-4-cyclohex
enyI-S-pyrazolone-4-methanesulphonic acid, 1
acids are readily decomposed, as may be recog
cyclohexyl-2.3 - dimethyl - 4 - amino-5-pyrazolone
nized by the odor of sulphurous acid shortly
4-methanesu1phonic acid. As organic solvents
there may, for instance, be used lower alcohols
and ketones, such as methyl alcohol, ethyl al
after the acidi?cation of the solutions of their
salts.
Now we have found that the aminomethyl
sulphonic acids of the pyrazolone series may be
obtained in a solid form from the corresponding
amine, formaldehyde and sulphurous acid or by
acidifying the salts of the corresponding amino
methanesulphonic acids, the operation being con
ducted in the presence of organic solvents with
complete or partial exclusion of-water. As meth
anesulphonic acids of the pyrazoloneamines there
may be used those having the amino group in
4-position, particularly those of the following
general formula:
40
I
R1
in which R1 stands for a six-membered aromatic
20
cohol, propyl alcohol, isopropyl alcohol, acetone,
methylethyl ketone, furthermore acetic ester and ‘
benzene. If the aminomethylsulphonic acid is
easily soluble in the organic solvent used for the
preparation, a second organic solvent such as
ether or the like may be used at any stage of the
process.
,
v
The process may, for instance, be carried out
by dissolving the amine in question in alcohol,
introducing the molecular proportion of sulphur
ous acid and then adding the molecular propor
tion of formaldehyde. After addition of a few
crystals the new acids then crystallize in most
cases. If not, the precipitation may be induced
by the addition of ether or another solvent. For
the execution of the process it is immaterial in
40
which sequence the different reactants are added.
It is, therefore, possible to cause the aminesul
phites ?rst prepared to react with the formalde- .
hyde or to cause the amines to react simultane
45 or hydroaromatic hydrocarbon radical, R2 for
ously with the formaldehyde and sulphurous
methyl or a six-membered hydroaromatic hydro
carbon radical and R3 for hydrogen, alkyl or a
siX-membered aromatic or hydroaromatic hydro
acid. The Schiff’s bases or the methylene-bis
compounds of the amines which may be produced
from the amines by reaction with the formalde
carbon radical, for instance, 1-phenyl-2.3-di
hyde may be transformed with sulphurous acid
methyl-‘l-methylamino-5-pyrazolone-4-methane
10
yl-2.3-dimethyl - 4 - ethylamino-5-pyrazolone-4 -
into the corresponding methylsulohonic acids;
59
2,128,512
2
in the latter case a further molecular proportion
of formaldehyde is added in order to completely
transform the amine into the methylsulphonic
acid. With a like success it is also possible to start
from the known alkali metal salts of the amino
methylsulphonic acids
of
pyrazolone-amines,
cc. of acetone and 64 grams of sulphurous acid
are introduced into the solution, while cooling.
On addition of '75 cc. of formaldehyde of 40 per
cent strength and of a few crystals, the meth
anesulphonic acid obtained according to example
1 crystallizes in an almost quantitative yield.
The acid obtained melts with decomposition at
made from the corresponding amines with the aid
of formaldehyde and alkalibisulphite (cf. Ger ' 131° C. to- 132D C.
The methanesulphonic acid obtainable accord
man patent speci?cation 421.505) and to acidify
the said alkali metal salts under the above stated ing to Examples 1 and 2 may be transformed into '
conditions. When causing pyrazoloneamines to‘ the corresponding sodium salt by means of caus
react with formaldehyde and sulphurous acid it
tic soda solution. The magnesium and calcium
is advantageous to work with solvents miscible. ‘salts may be obtained in a similar way.
(3) 147 grams of 1-phenyl-2.3-dimethyl—4
with water. When causing methanesulphonic
acid salts to react with acids it is also possible to >benzylamino-S-pyrazolone are dissolved in 1000
work in the presence of a solvent which is not
cc. of absolute alcohol and 38 cc. of formaldehyde
of 40 per cent strength are added, while cooling.
It is important for the process of this invention v32 grams of sulphurous acid are introduced, while
that no substantial amount of water be present.v further cooling. After some time the l-phenyl
When causing pyrazolone amines to react with 2.3-dlmethyl-4 - benzylamino - 5 — pyrazo-lone - 4
formaldehyde and sulphurous acid the presence methanesulphonic acid crystallizes in a yield of 90
of water cannot be entirelyavoide'd, ‘since the per cent. The point of decomposition is at 133° C.
(4) 35 grams of the sodium salt of 1-phenyl
formaldehyde must be added in the form of an
aqueous solution, The amount of water inthe ;2.3edimethyl-4-methylamino - 5 - pyrazolone - 4 25 total volume of the reaction mixture should, " methanesulphonic acid are dispersed in 200 cc. of
however, not exceed 5 per cent. When causing alcohol and the solution is mixed with 100 grams
the salts of methanesulphonic acids to react with of an alcoholic hydrochloric acid of 3.6 per cent
strength. When the reaction is complete the
mineral acids it is possible to work in the com
whole is ?ltered. After a short time the meth—
plete absence of water.
The process of our present invention involves anesulphonic acid described in Examples 1 and 2
30
various advantages. It is practically dif?cult to crystallizes out. Decomposition point 131° C. to
miscible with water.
7
produce in a pure form the monoalkylamino-py
razolones as they are utilized for the manufacture
123° C.
(5) 45 grams of 1-cyclohexyl-2.3-dimethyl-4
of pharmaceutical products, since the secondary
methylamino-5-pyrazolone (‘obtainable according
35 bases are frequently contaminated with tertiary
to the co-pending application Serial No. 709,232,
?led January 31, 1934, in the name of Max Bock
and primary bases. The present invention offers
the possibility of directly obtaining from a crude
mixture of amines the methylsulpho-nic acids of
the desired. secondary bases. By condensing, for
40 instance, the crude product of 4-methylamino-1
phenyl - 2.3 - dimethylpyrazolone containing ' be
miihl and Walter Krohs) are dissolved in 250 cc.
of absolute alcohol, 15 cc. of formaldehyde of 40
per cent strength are added and 13 grams of sul
phurous acid are introduced into the solution, 40
while cooling. On addition of ether the l-cyclo
sides the secondary amine quantities of primary
and tertiary amine, with formaldehyde and sul
lone-4-methanesulphonic acid crystallizes. Point
phuric acid in an alcoholic solution, the omega
methanesulphonic acid of 4-methylaminopyrazo
lone which is comparatively more, sparingly solu
ble precipitates very soon, whereas the homolo
gous compound and the tertiary base remain
dissolved. Since the omega-aminoethanesul
50 phonic acids may easily be transformed with the
aid of an alkali into their salts, chemically pure
salts of the omega-methanesulphonic acid of sec
hexyl-2.3-dimethyl-4 - methylamino -‘ 5 - pyrazo
of decomposition 153° C. to 154° C. Yield 90 per
HR El
cent.
(6) 223 grams of 4.4'-methylene-bis-l-phenyl
2.3-dimethyl-4-methylamino-5-pyrazolone of the
following formula:
ondary pyrazolone-amines may easily be ob
tained by starting from a mixture of amines of
55
the 4-amino—pyrazolones.
Furthermore the aminomethanesulphonic acids
according to our present invention are intended
to be used for the manufacture of new phar
60
maceuti cal products.
The following examples illustrate the inven
tion:
(1) 219 grams of 1-phenyl-2.3-dimethyl-4
methylamino-5-pyrazolone are dissolved in 1000
cc. of absolute alcohol and after addition of 75
65 cc. of formaldehyde of 40 per cent strength 64
grams of sulphurous acid are introduced, while
cooling. By continued cooling, the l-phenyl-2.3
dimethyl-4-methylamino-5—pyrazolone~4 - meth
anesulphonic acid crystallizes after some time.
70 The well crystallized acid is ?ltered by suction
and subsequently washed with a small quantity
of alcohol. The yield is almost quantitative; the
point of decomposition is at 131° C. to 132° C.
(2) 219 grams of 1-phenyl-2.3-dimethyl-4
75 methylamino-5-pyrazolone are dissolved in 1000
and 37.5 cc. of formaldehyde of 40 per cent
strength are dissolved in 1000 cc. of alcohol and
64 grams of sulphurous acid are introduced into
the cooled solution. After a short time the 1
phenyl-2.3-dimethyl-4-methylamino - 5 - pyrazo
60
lone-4-methane-sulphonic acid described in Ex
amples 1 and 2 crystallizes out. The yield is
quantitative. Point of decomposition 131° C. to
132° C.
(7) 22 grams of 1-cyclohexyl-2.3-dimethyl-4
amino-5-pyrazolone are dissolved in 100 cc. of ab
solute alcohol and the solution is mixed with 7.8
cc. of a solution of formaldehyde of 40 per cent
strength and 4 grams of sulphurous acid. On
cooling, the free 1-cyclohexyl-2.3-dimethyl-4
amino-5-pyrazolone - 4 - methanesulphonic
70
acid
crystallizes in a yield of 90 per cent strength.
We claim:
1. The process which comprises causing formal
dehyde and sulphurous acid to act upon l-phenyl
75
3
2,128,512
2.3 - dimethylamino~4-methylamino-5-pyrazolone
5. The processwhich comprises causing formal
in the presence of ethyl alcohol and in the ab
dehyde and sulphurous acid to act upon a com
sence of a substantial amount of. water and isolat
pound of the ‘following general formula:
ing the free sulphonic acid.
'
2. In the process of’ preparing omega-methane
sulphonic acids of 2.3-dialkyl-4-amino-pyrazo
lones the steps which comprise conducting the
step which directly leads to the formation of the
free omego-methanesulphonic acid in the pres
ence of an organic solvent in which said acids
10
are substantially insoluble, selected from the class I in which R1 stands for a radical of. the group con
consisting of low molecular aliphatic alcohols, low sisting of six-membered aromatic and hydro~
molecular aliphatic ketones, acetic ester, benzene aromatic radicals and R3 for a member of the
and ether in the absence of a substantial amount group consisting of hydrogen and six-membered
15 of water, and isolating the free sulphonic acid.
aromatic and hydroaromatic hydrocarbon radi
15
3. In the process of preparing compounds of the
cals, in the presence of an organic water-soluble
following general formula:
solvent in which said acids are substantially in
soluble, selected from the class consisting of low
molecular aliphatic alcohols, low molecular ali
phatic ketones, acetic ester, benzene and ether,
and in the absence of. a substantial amount of
t.
25 in which R1 stands for a radical of the group
consisting of. siX-membered aromatic and hydro
aromatic hydrocarbon radicals, R2 for a member
of the group consisting of methyl and a six
water and isolating the free sulphonic acid.
6. A free omega-methanesulphonic acid of a
2.3-dialykl-4-amino-pyrazolone in a dry, solid,
crystalline form, which is easily soluble in water
and decomposes when melted.
'7. A free omega-methane-sulphonic acid of the
following general formula:
membered hydroaromatic hydrocarbon radical
and R3 for a member of the group consisting of
30
hydrogen, alkyl and six-membered aromatic and
hydroaromatic hydrocarbon vradicals, the steps
which comprise conducting the step which leads
to the formation of the free omega-methanesul
phonic acid in the presence of. an organic solvent
in which said acids’ are substantially insoluble,
selected from the class consisting, of low molecular
aliphatic alcohols, low molecular aliphatic ke~
tones, acetic ester, benzene and ether, and in the
40 absence of a substantial amount of water and
isolating the free sulphonic acid.
4-. In the process of preparing compounds of
the following general formula:
in which R1 stands for a radical of the group con
35
sisting of six-membered aromatic and hydro
aromatic hydrocarbon radicals, R2 for a member
of the group consisting of methyl and a six
membered hydroaromatic hydrocarbon radical
and R3 for a member of the group consisting of
hydrogen, alkyl and six-membered aromatic and
hydroaromatic hydrocarbon radicals, in a dry,
' solid, crystalline form, which is easily soluble in
water and decomposes when melted.
45
8. A free omega-methanesulphonic acid of the 45
following general formula:
l
R:
in which R1 stands for a radical of the group con
sisting of six-membered aromatic and hydroaro
N
matic radicals and R3 for a member of the group
consisting of hydrogen and six-membered aro
55
l
.R‘
matic and hydroaromatic hydrocarbon radicals,
the steps which comprise conducting the step
in which R1 stands for a radical of the group con
which leads to the formation of the free omega
methanesulphonic acid in the presence of an or
ganic solvent in which said acids are substantially
aromatic radicals and R3 for a member of the
insoluble, selected from the class consisting of. low
60 molecular aliphatic alcohols, low molecular ali
phatic ketones, acetic ester, benzene and ether,
and in the absence of a substantial amount of
water and isolating the free sulphonic acid.
'
sisting of six-membered aromatic and hydro
group consisting of hydrogen and six-membered
aromatic and hydroaromatic hydrocarbon radi
cals, in a dry, solid, crystalline form, which is
easily soluble in water and decomposes when 60
melted.
-
'
MAX BocKMiiHL.
LEONHARD STEIN.
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