Note: Descriptions are shown in the official language in which they were submitted.
12~8474
This invention relates to acid addition salts of 2-[(2-
aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran of the formula
(I)
N-Cil2 ~ ~ C~z-S-(CH2)2 2
and a process for preparing same a:nd, if desired, for
transforming any of the salts obtained to the base of formula
(I). The inventlon also relates to an intermediate for preparing
u the above compounds. More particularly, it relates to the
zwitterionic ~5-dimethylaminomethyl-2-furylmethyl) hydrogen
sulphate of formula (III)
~ ~-CH2 ~ CH2-O_So3 ~III)
CH3
as well as to a process for the preparatlon thereof.
2U The compound of formula (I) and lt~ acid addition salts
are intermediates for preparing 1-~2-[5-dimethyl-
2~
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~L26847~
-- 2 --
aminomethyl-2-(furylmethylthio)-ethyl7}-amino-1-methyl-
amino-2-nitroethylene of the formula (II)
CH~3 ~
~ H2 ~ 0 ~ CH2-s-(c~l2)2-NH-c-NH-cH3 (II)
CH3 CHN02
which is a known, outstanding drug against gastric and
duodenal ulcers ~Brit. J. Pharmacol. 72, 49, 55 /1981/).
For preparing the base of formula (I), two processes
are described in the published German patent application
No. 2,734,070. Hereinafter, these processes will be named
as "literature process A" and "literature process B",
respectively.
According to the literature process A, reported
in Example A/ (page 37) of the patent application cited
above, a mixture containing cysteamine hydrochloride, 5-
^ -dimethylaminomethyl-2-furfuryl alcohol of the formula (IVj
20 ~ -CH2 ~ CH2-OH (IV)
CH3
and concentrated hydrochloric acid is kept at 0 G for
18 hours. In this reaction, the hydrochloric acid is
present in an about 10-fold molar excess. After the work-
ing-up and dist~illation, the base form of formula (I3 is
obtained with a yield of about 54 e~.
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~2~i~474
-- 3 --
It was shown by own experiments that this moderate
yield is a consequence of the extremely acidic medium;
namely, under these conditions the reaction is accompanied
by an intensive tar formation.
It should be noted that the sensitivity of the
furan derivatives to acids is well-known in the literature
(see e.g. Rodd's Chemistry of Carbon Compounds, Ed. S.
Coffey, Vol. IV/A, page 91, Elsevier Co., New York, 1973).
The disadvantages of this process are as follows.
- The duration of the reaction necessary to prepare the
compound of formula (I) is too long.
- The reaction medium is extremely corrosive.
- The base of formula ~I) obtained after distillation is
unstable even when kept in refrigerator at a temperature
between 0 and 4 C: after a few days it becomes dark.
; Thereafter it is not uniform, i.e. it becomes unsuitable
for further use within a relatively short period. The
instability - particularly to heat - of the free base
of formula (I~ is well demonstrated by the fact that
at most 60 to 70 % can be recovered without decomposition~
even when the uniform, pure base is subjected to distill~
tion under highly reduced pressure and at relatively
low temeprature, e.2. at 120 to 124 C and a pressure
of 80 to 107 Pa.
For these reasons (in conclusion~ the literature
process A lS not suitable for lar~e-scale produc~ion.
The literature process B is only partially reported
in the Example D/ (page 40) , Example E/ ~page 41) and
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~L2~474
Example 1 (page 48~ of the patent application cited above.
According to these Examples, the base of formula lI) is
prepared in three steps. In the first step ~Example D/ on
page 40), 2-furylmethyl mercaptan is condensed with N-(2-
bromoethyl~-phthalimide to give 2-(2-phthalimidoethyl~-
-thiomethylfuran in a yield of 52.3%; in the second step
~Example E/ on page 41~, this product is brought into
Mannich reaction with dimethylamine hydrochloride and form-
aldehyde to give 2-/~2-phthalimidoethyl~-thiomethyl7-5-di-
methylaminomethylfuran, i.e. the phthaloyl derivative ofthe compound of formula (I~ with a yield of 47.3%; final-
ly, in the third step this latter compound is dephthaloylat-
ed (Example 1 on page 48) to give the salt of the base
of formula ~I) with phthalic acid hydrazide. The separation
of the compound of formula (I) and the yield are not given;
thus, the literature process B cannot be used for comparison.
; It has been found withln own experiments that the yield of
the third step, i.e. of dephthaloylation, cannot be
considered as more than 84%. In conclusion, the overall
yield of the literature process B, as calculated for 2-
-furylmethyl mercaptan as starting material used in the
first step, is at most 20.78% of the base of formula (I).
For a complete comparison of literature processes
A and B it is suitable to trace back both the starting
material of the literature process A, i.e. the compound of
formula (IV) , as well as that of the literature process B,
i.e. 2-furylmethyl mercaptan to 2-furfuryl alcohol, i.e.
to the common, commercially available base material Or both
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~.26~47~
starting compounds. The yield, known from the literature, of the
compound of formula (IV) is 70% as calculated for 2-furfuryl
alcohol (J. Chem. Soc. 1958, 4728), while the yield, known from
the literature, of 2-furylmethyl mercaptan is 60% as calculated
for 2-furfuryl alcohol ~Organic Sytheses Coll. Vol. 4, page 491,
John Wiley and Sons, Inc., New York, 1963).
~i
Obviously, out of the two processes known from
literature, the literature process A is unambiguously more
preferable since in this way the base of formula (I) is obtained
from the common, commercially available base material in less
:Lu steps and in a higher overall yield ~i.e. 37.8%) as compared to
the overall yield (i.e. 12.47%) of the literature process B.
However, as indicated above, the literature process B also shows
a number of disadvantages, mainly from the view-point of large
scale production.
1~;
: Thus, the present invention provides a process for the
preparation of the compound of formula (I~ and/or of the acid
addition salts thereof, which is devoid of the drawbacks of the
above-sighted processes known in the prior:art, and makes z~ possible to produce the compound of formula ( I ) and~or the acid
addition salts thereof in a good yield and in a simple way at an
industrial scale, too.
~` Now it has been found, unexpectedly, that the compound ~ of formula ~I) can be prepared in a much more advantageous way
than via the processes reported above,
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-- 6 --
by reacting cysteamine or an acid addition salt thereof
with the new, zwitterionic ~5-dimethylaminomethyl-2-
furylmethyl) hydrogen sulphate of formula ~III), which
latter can in turn be obtained from 5-dimethylaminomethyl-2-
-furfuryl alcohol of the formula ~V) in an excellent yield.
Further on, it has been found that the base of formula (I~,
which can directly be used for the preparation of the
compound of formula (II), or any desired acid addition salt
of the base of formula ~I) can easily be obtained in a good
quality from the new salts thereof prepared in this way.
The in~ention also relates to the preparation of the
new, zwitterionic (5-dimethylaminomethyl-2-furylmethyl~
hydrogen sulphate of formula (III) used in the process of
the invention.
Thus, the present invention relates to the acid
addition salts of 2-/~2-aminoethyl~-thiomethyl7-5-dimethyl-
aminomethylfuran of the formula (I) and a process for prepar-
ing same and, if desired, for transforming any of the
salts obtained to the ~no~ base of formula (I), which
comprises
a/ reacting the zwitterionic (5-dimethylaminomethyl-
-2-furylmethyl) hydrogen sulphate of formula ~III) with
cysteamine or with an acid addition salt thereof, or
b/ treating 5-dimethylaminomethyl-2-furfuryl alcohol
of the formuLa (IV) with sulphur trioxide or with an agent
suitable to introduce sulphur trioxide in the presence of a
solvent, then separating and reacting the obtained ~5-di-
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-- 7 --
methylaminomethyl-2-furylmethyl) hydrogen sulphate of
formula (III) with cysteamine or with an acid addition
salt thereof
and, if desired, separating the acid addition salt of the
base of formula (I) obtained by process a/ or bJ and/or,
if desired, liberating therefrom the base of formula (I),
purifying it and/or, if desired, transforming it to another
acid addition salt of the base of formula (I).
A preferred embodiment of process a/ of the invention
comprises melting the zwitterion of formula ~III) with an
acid addition salt (e.g. with the hydrochloride) of
cysteamine under nitrogen or under vacuum at a temperature
between 60 and 95 C without adding any solvent.
Ihe process of the invention can preferably be
carried out in the presence of solvents, too.
A preferred embodiment of process b~ of the invention
` comprises reacting 5-dimethylaminomethyI-2-furfuryl alcohol
of the formula ~IV~ with a complex formed from dimethyl-
formamide and sulphur trioxide and used in a nearly 1~
molar proportion in dimethylformamide as solven~. As the
reaction proceeds, the zwitterionic compound of formula ~III)
~; is precipitated from the mixture as a solid and it can
easily be separated after termination of the reaction.
~` The zwitterionic compound separated can preferably be
brought into reaction with cysteamine or with an acid
addition salt thereof.
In the process b/ of the invention the zwitterionic
compound of formula (III) may also be formed in aceto-
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~ 8 --
nitrile or carbon tetrachloride, instead of dimethyl-
formamide.
After alkalization of an aqueous solution of the
melt obtained either in process a/ or b/ of the invention,
the composition of which accords to a mixed monohydro-
chloride monohydrogen sulphate salt of the base of
formula (I), the base of formula (I) can be extracted
into an organic solvent. The crude base of formula (I),
obtained as the evaporation residue of the organic extract,
or the pure base of formula (I) obtained therefrom by
distillation can be transformed to any desired acid addi-
tion salt of the base of formula ~I) after adding the
appropriate acid component. However, the salt of the base
of formula (I~ formed in either process a/ or b/ of the
invention can be transformed also directly, without
liberating the base to another acid addition salt of the
base of formula t I).
As an example for the transformation of an acid
addition salt of the base of formula (I~, obtained by
either process a/ or b/ of the invention, to another acid
addition salt thereof, the hydrochloride may preferably be
prepared by separating first the base of formula ~I) in the
manner of working-up mentioned above and then by acidify-
ing a solution thereof in a lower aliphatic alcohol, e.g.
in ethanol with a solution of dry, gaseous hydrogen
chloride in the appropriate lower alkanol. Thus, the di-
hydrochloride of the base of formula (I) is obtained as a
crystalline precipitate.
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A monohydrochloride can also be formed from the
base of formula (I) in a known manner.
Cysteamine and its salts, used both in the processes
a/ and b/ of the invention, are known compounds, a part of
which is commercially available.
Instead of the complex formed from sulphur trioxide
and dimethyl formamide, the complex of sulphur trioxide
with pyridine or dioxane, respectively, may also be used
for the process b/ of the invention. A11 these complexes
are known from the literature / see e.g. J. Am. Chem. Soc.
~ 81, 1764 (1959~; Chem. and Ind. 1966, 9007.
i 5-Dimethylaminomethyl-2-furfuryl alcohol of the
formula ~V 3 , used in process b/ of the invention, is
also a compound known from the literature / J. Am. Chem.
Soc. 69, 464 ~1947~7.
¦ The advantages of the process of the invention can
¦ be summarized as follows.
- Unlike in the known literature process A, no large
amounts of a concentrated mineral acid are required for
the reaction; thus, the danger of corrosion is significan~
ly lower.
- It is mainly due to the elimination of the strong acid
; ~ that, according to the process of the invention, the
reaction temperature can significantly (e.g. from 0 C
to 90 C) be increased wlthout any deterioration in the
quality of the product, whereby the time of reaction is
also significantly (at least by an order of magnitude)
diminished. All these factors contribute to the formation
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-- 10 --
of a tar-free product of good quality.
- The salts of the base of formula (I) prepared accord-
ing to the process of the invention are well-defined,
stable substances from which, if desired, the base of
formula (I) can be liberated at any time, in a suitably
short time before use.
- Some of the acid addition salts of the base of formula (I)
prepared according to the process of the invention may
directly (i.e. without liberating the base) be employ-
ed for preparing 1 {2-/ 5-dimethylaminomethyl-2-~furyl-
methylthio)-ethyl7~-amino-1-methylamino-2-nitroethylene
of the formula (II~.
- The volume needed for the reaction is significantly di-
minished by eliminating the excess of the acid, i.e. by
carrying out the reaction through melting; thus, the
efficiency of utilization of the equipment capacity
becomes higher.
- While preparing 5-dimethylaminomethyl-2-furfuryl alcohol
of the formula (IV~ according to the literature / J. Am.
Chem. Soc. 69, 464 (1947L7 the distilled base of
formula (IV) contains a high amount ~in some cases 10
to 20%) of contaminating materials. When the compound
of formula (IV) obtained in this way is directly trans-
formed to the base of formula (I~ according to the
process described in Example A/ (page 37) of the publish-
ed German patent application No. 2,734,070, a significant
amount o~ contaminations, mainly tars,are formed owing
to the hi~sh excess of the acid during the reaction,
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~6~347~
-- 11
even when the reaction temperature is low. In contrast
to this, when a product of the formula (IV) is trans-
formed to the new zwitterionic compound of formula ~
according to the process of the invention, the contamina
tions arising durin~ the preparation of the compound
of formula (IV) and influencing disadvantageously the
reaction of the compound of formula ~V)with cysteamine
hydrochloride are retained in the mother liquor remain-
ing after filtering out the zwitterionic substance;
hence, the reaction with cysteamine or with an acid
addition salt thereof, carried out in the following
step, is not disturbed.
- According to the literature process A, the yield of the
distilled base of formula (I) as calculated for the
compound of formula (IV~ is about 54%. As the zwitter-
ionic compound of formula (III~ is obtained from the
compound of formula (IV) in a 92.8% yield and the
compound of formula (III) can be transformed to the
base of formula (I) with a yield of 68 . 9% according to
the process of the invention, the overall yield of the
distilled base of formula (I) as calculated for the
compound of formula (IV 3 is 6~ . 9~, i.e. much better
than the yield of the literature process A.
It is obvious that the use of the process of the
invention at an industrial scale is made possible on the
basis of the advantages summariæed above.
The process of the invention i5 illustrated in detail
by the following non-limiting Examples.
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~X68474
- 12 -
Preparation of the starting materialt i.e. t5-di-
methylaminomethyl-2-furylmethyl) hydrogen sulphate
/ zwitterion of the formula ~III)7
Example 1
Step A/
Preparation of the complex formed from sulphur tri-
oxide and dimethylformamide (DMF.S03)
40 to 50 g (0.50 to 0.62 mole) of liquid S03 are
portionwise added to 152 g ~2.0 moles) of dimethylformamide
under stirring and cooling at such a rate that the temperature
of the reaction mixture does not exceed 20 C. Then the
mixture is cooled below 5 C, whereupon a portion of the
complex crystallizes out. After filtering by suction, the
complex contains 5.80 to 6.40 mmoles/g of sulphur trioxide
according to the analysis.
Step B/
Preparation of (5-dimethylamlnomethyl-2-furylmethyl)
hydrogen sulphate
To a solution containing 258 ml of acetonitrile and
22.70 g ~143.2 mmoles) of the filter-wet dimethylformamidè-
-sulphur trioxide complex, prepared according to step A/,
22.23 g (143.2 mmoles) of 5-dimethylaminomethyl-2-furfuryl
alcohol are added while stirring and cooling at such a rate
that the internal temperature remains between 15 and 20 C.
Then 258 ml of acetonitrile are added and the mixture is
kept at 4 C overnight. The crystalline precipitate is
filtered off by suction, washed with acetonitrile and dried
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~6~74
to give 17.30 g (51.3%) of the aimed product, m.p. 179
to 181 C.
Example 2
9.93 g (124.02 mmoles) of sulphur trioxide are
introduced to 190 ml of anhydrous dimethylformamide under
anhydrous conditions, while stirring and coolln~ at such
a rate that the inner temperature of the reaction does not
exceed 20 C. Then 19.25 g (124.02 mmoles3 of 5-dimethyl-
aminomethyl-2-furfuryl alcohol of the formula tIV) are
added to the reaction mixture while stirrinæ and continuous
cooling at such a rate that the inner temperature remains
below 20 C. When the addition is complete, the mixture is
stirred at the same temperature for 30 minutes and kept ;:!
at 0 to 4 C overnight. The precipitate is filtered off by
suction, washed with anhydrous dimethylformamide, then
with ether and dried at room temperature under reduced
pressure and anhydrous conditions to give 27.10 g (92.8%~
of the zwitterionic substance of formula ~ , m.p. 173
to 181 C.
Preparation of 2-/72-aminoethyl)-thiomethyl7-5-dl-
methylaminomethylfuran of the formula (I) and its
acid addition salts
Example 3
~reparation of the monohydrochloride monohydrogen
sulphate mixed salt of 2-/~2-amlnoethyl)-thiomethyl7-
s~
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_ 14 -
-5-dimethylaminomethylfuran base of the formula (I)
A mixture containing 24.70 g (105 mmoles) of the
zwitterionic (5-dimethylaminomethyl-2-furylmethyl) hydrogen
sulphate of formula (III) and 11.36 g (100.0 mmoles)
of cysteamine hydrochloride is heated in a bath kept at
90 to 92 C while stirring under dry nitrogen atmosphere
for 2.5 hours. After cooling the homogeneous melt solidifies
and 35.90 g of a solid are obtained analytical data of
which essentially correspond to the aimed mixed salt.
clOH2lclN2o5s2
Calculated: Cl 10.16; N 8.03; S04 27.53~;
Found: Cl 10.03; N 7.73; S04 27.03~.
Ex~mple 4
Preparation of 2-/¦2-aminoethyl)-thiomethyl7-5-di-
methylaminomethylfuran / the base of formula (I)7
A/ Preparation of a crude base of formula (I)
The melting reaction is carried out in a similar
manner and with the same quantities as described in Example
3. After terminating the reaction the melt is cooled down,
dissolved in 20 ml of water and the pH value of the solu-
tion is adjusted to 9 by adding 4N aqueous potassium
hydroxide solution under cooling. After decolouring with
activated carbon while stirring in a water bath kept at
50 to 60 C, the solution is filtered and then extracted
5 times with 150 ml of dichloromethane each. The organic
extracts are combined, dried over anhydrous sodium sulphate
and evaporated. The crude base obtained ~1.21 g; 94.26%
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5 --
as calculated for the zwitterionic compound of formula (II~
and 98.9% as calculated for cysteamine hydrochloride7 as
the evaporation residue is a pale yellow oil, n20 - 1.5205.
A small sample of the crude base boils at 116 to 120 C/13.3 Pa.
B/ Preparation of a distilled base of formula (I 3
The melting reaction is carried out in a similar
manner and with the same quantities as described in Example 3.
After carrying out the reaction, the melt is dissolved in
100 ml of water while hot, the pH value of the solution is
adjusted to 9 by adding 4N aqueous potassium hydroxide solu-
tion under cooling with ice, decoloured with activated
carbon in a water bath kept at 50 to 60 C and after
filtration it is extracted 3 ti~es with 300 ml of chloro-
form each, while the pH value of the aqueous phase iscontinuously kept at 9 by adding 4N aqueous potassium
hydroxide solution. The organic extracts are combined, dried
over anhydrous sodium sulphate, and after removing the
drying agent the solution is evaporated in a water bath
kept at 50 C. The crude base residue is distilled to give
15.73 g / 68.9% as calculated for the æwitterionic compound
of formula ~III) and 73.3~ as calculated for cysteamine
hydrochloride7 of the base of formula (I) as a main
fraction, b.p. 80 to 85 C/6.66 Pa~ n20 _ 1.5255.
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~2~474
6 --
Exam~e 5
Preparation of the dihydrochloride of 2-/12-amino-
ethyl)-thiomethyl7-5-dimethylaminomethylfuran base
of the formula ~I~
The melting reaction is carried out in a similar
manner and with the same quanti.ties as described in
Example 3. The working-up and t;he separation of the crude
base are accomplished according to Example 4A. The crude
base, weighing 21.13 g, obtained as an evaporation residue
is dissolved in 50 ml of anhydrous ethanol, and ethanol
containing dry hydrogen chloride is added in little por-
tions under cooling with ice until a pH value of 2 is
reached. The mixture is kept at 0 to 4 C overnight, the
crystalline precipitate is filtered off by suction, wash-
ed with ice-cold anhydrous ethanol and dried at room
temperature to give 23.2 g / 76.9% as calculated for the
zwitterionic compound of formula (III) and 80.7Yo as
calculated for cysteamine hydrochloride7 of the aimed
product, m.p. 153 to }58 C. This crude product is re-
crystallized from 120 ml of hot ethanol under decolour-
ing with activated carbon, the solution obtained after ~:
filtration is concentrated to a volume of 80 ml, 3 ml of
ethanol containing 8% of dry hydrogen chloride are added
and the mixture is kept at 0 to 4 C overnight. The
crystalline precipitate is filtered by suction and thentreated as described above to give 17.85 g / 59.1% as
calculated for the zwitterionic compound of formula (III)
and 62.1~ as calculated for cysteami:ne hydrochloride7
'
~;~68474
7 --
of the aimed product, m.p. 160 to 162 C.
Example 6
Preparation of the monohydrochloride of 2-/t2-amino-
ethyl)-thiomethyl7-5-dimethylaminomethylfuran base
of the formula (I)
A solution of 21.4 g ~0.1 mole) of 2-~ 2-amino-
ethyl~-thiomethyl7-5-dimethylaminomethylfuran base of
formula (I~, prepared according to Example 4B, in 50 ml
lQ of methanol is added dropwise to the solution of 28.7 g
(0.1 mole~ 2-/~2-aminoethyl)-thiomethyl7-5 dimethylamino-
methylfuran dihydrochloride, prepare~ according to Example 5,
in 300 ml of methanol, then the mixture is stirred for ten
minutes and evaporated to dryness under reduced pressure.
The residue is triturated with 100 ml of ether, kept at 0
to 4 C for 2 hours, filtered, washed with ether and dried
at 20 C to give 48 g (89%3 of the aimed product, m.p. 111 :~
to 112 C.
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