CA1268474A - Process for preparing a basic thioether and the salts thereof - Google Patents
Process for preparing a basic thioether and the salts thereofInfo
- Publication number
- CA1268474A CA1268474A CA000480665A CA480665A CA1268474A CA 1268474 A CA1268474 A CA 1268474A CA 000480665 A CA000480665 A CA 000480665A CA 480665 A CA480665 A CA 480665A CA 1268474 A CA1268474 A CA 1268474A
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- base
- acid addition
- addition salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to the acid addition salts of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran of the formula (I) and a process for preparing same and, if desired, for transforming any of the new salts obtained to the known base of formula (I). The process 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 an agent suitable to introduce sulphur trioxide in the presence of a solvent, then separating and reacting the obtained (5-dimethylaminomethyl-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 b) and/or, if desired, liberating therefrom the base of formula (I), purifying it and/or transforming it to an other acid addition salt of the base of formula (I).
The compound of formula (I) and its acid addition salts are intermediates for preparing 1-{2-[5-dimethyl-aminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methyl-amino-2-nitroethylene of the formula (II) which is a known drug against gastric and duodenal ulcers.
The invention relates to the acid addition salts of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran of the formula (I) and a process for preparing same and, if desired, for transforming any of the new salts obtained to the known base of formula (I). The process 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 an agent suitable to introduce sulphur trioxide in the presence of a solvent, then separating and reacting the obtained (5-dimethylaminomethyl-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 b) and/or, if desired, liberating therefrom the base of formula (I), purifying it and/or transforming it to an other acid addition salt of the base of formula (I).
The compound of formula (I) and its acid addition salts are intermediates for preparing 1-{2-[5-dimethyl-aminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methyl-amino-2-nitroethylene of the formula (II) which is a known drug against gastric and duodenal ulcers.
Description
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) 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-
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~
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) 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) 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~.
:
'~ ~ ' ",' ~2~i~474 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 , , .
` '.,.'' " '~ ' ` ' ' ~ ' ~' ~.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,
' : .
:' :
X;" ' ~ .
- - .. , .. ~ .: . ~
~L26847~
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) 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) 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~.
:
'~ ~ ' ",' ~2~i~474 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 : :
.
. :
- . , .
: ; ; : ~` . .,''', ' ~: '; ' - . ', . ' : :
., .
~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 , , .
` '.,.'' " '~ ' ` ' ' ~ ' ~' ~.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,
3 3~
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-~LZ6~3474 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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:~2tj847 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-` ` I :
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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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_ g _ 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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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, ::
' ` '' "' '; ' , ' ; ~ ' ~6~347~
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 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 :
.,i I
:. .. -: ~: : :: : , :...... ..
:: : : . :
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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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~ X ~7 _ 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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~X~B4~4 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.
, . .
'' , : :
`' ' ~ "
~2~474 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 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.
~ ~, , " . ~ :
..--- :-..
~ 5 ~
~, .
~- .
.. . ... . .
-~LZ6~3474 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-:~ :
.~ -. - . .
:: .- . ~
:, . - ,,.,, : - ~', :
:~2tj847 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-` ` I :
... , . :. ., :., : ~ :
- - . : :' ` .,:.. : , , lZ~1~47'~
~ 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.
:` ~:::
:
~: . .. . ... ., .. =, . , . - . :
:: .: :. , .-~ ~ 6~4 7L~
_ g _ 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 ;
..
" : ::
7~
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, ::
' ` '' "' '; ' , ' ; ~ ' ~6~347~
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.
I
: : : " ;::
.. ..
- :: " - ~
.
.:~, . :~ -~X68474 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 :
.,i I
:. .. -: ~: : :: : , :...... ..
:: : : . :
. : ~ :i: ' ,' ,... : , : .: .. ;, ~ : : ~
~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~
- .;. ,~
: . . . :
, --- ~.' ';., ~ ', ' ' :
~ X ~7 _ 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%
.. . . - , , . .: ::~, ~ . - -. .
.. ,. ~ .,: . :
~X~B4~4 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.
, . .
'' , : :
`' ' ~ "
~2~474 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 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.
~ ~, , " . ~ :
..--- :-..
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of acid addition salts of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran of the formula (I) (I) which comprises (a) reacting the zwitterionic (5-dimethylamino-methyl-2-furylmethyl) hydrogen sulphate of formula (III) (III) with cysteamine or with an acid addition salt thereof, or (b) treating 5-dimethylaminomethyl-2-furfuryl alcohol of the formula (IV) (IV) with sulphur trioxide or a complex formed from sulphur trioxide in the presence of a solvent, then separating and reacting the obtained (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulphate of formula (III) with cysteamine or with an acid addition salt thereof and, when required, separating the acid addition salt of the base of formula ( I ) .
2. A process as claimed in claim 1, which comprises reacting the zwitterionic (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulphate of formula (III) with cysteamine or with an acid addition salt thereof in the absence of any solvent.
3. A process as claimed in claim 1, which comprises carrying out the reaction at a temperature between 60°C and 90°C.
4. A process as claimed in claim 1, 2 or 3, which comprises using cysteamine hydrochloride as an acid addition salt of cysteamine.
5. A process as claimed in claim 1, process (b), which comprises using the complex formed from sulphur trioxide and diemthylformamide.
6. A process as claimed in claim 1 or 5, which comprises using dimethylformamide, acetonitrile or carbon tetrachloride as solvent for preparing the zwitterionic compound of formula (III).
7. A process as claimed in claim 1, which comprises liberating the base of formula (I) and purifying said base.
8. A process as claimed in claim 7, in which the base is converted into an acid addition salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU841690A HU198196B (en) | 1984-05-02 | 1984-05-02 | Process for production of basic tioether and its salts |
| HU1690/84 | 1984-05-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1268474A true CA1268474A (en) | 1990-05-01 |
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ID=10955710
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|---|---|---|---|
| CA000480665A Expired - Fee Related CA1268474A (en) | 1984-05-02 | 1985-05-02 | Process for preparing a basic thioether and the salts thereof |
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| Country | Link |
|---|---|
| KR (1) | KR920005828B1 (en) |
| AR (1) | AR240455A1 (en) |
| AT (1) | AT387573B (en) |
| CA (1) | CA1268474A (en) |
| CS (1) | CS259878B2 (en) |
| DK (1) | DK196785A (en) |
| ES (1) | ES8609292A1 (en) |
| FI (1) | FI88501C (en) |
| GR (1) | GR851062B (en) |
| HU (1) | HU198196B (en) |
| IT (1) | IT1200464B (en) |
| MX (1) | MX161373A (en) |
| NO (1) | NO168942C (en) |
| PT (1) | PT80382B (en) |
| SU (1) | SU1375133A3 (en) |
| YU (1) | YU45714B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
| CH640846A5 (en) * | 1977-07-29 | 1984-01-31 | Allen & Hanburys Ltd | Aminoalkylfuran derivative |
| ES497514A0 (en) * | 1980-12-05 | 1981-10-16 | Liade Sa Lab | PROCEDURE FOR OBTAINING A HETEROCICLICAL PRIMARY AMINE DERIVATIVE |
| ES8300732A1 (en) * | 1981-06-10 | 1982-11-01 | Lafarquim | Procedure for the obtaining of derivados de furil mettil mercaptano and its salts of pharmacological interest (Machine-translation by Google Translate, not legally binding) |
| ES8206505A1 (en) * | 1981-10-21 | 1982-08-16 | Liade Sa Lab | Procedure for obtaining a heterociclic derivative of dimethylamine and its physiologically acceptable salts. (Machine-translation by Google Translate, not legally binding) |
| ES8301226A1 (en) * | 1981-11-20 | 1982-11-16 | Especialidades Latinas Medic U | Procedure for obtaining N- (2-5-dimethylamine, methyl-2-furanyl-methyl-thio-ethyl-n'-methyl-s-nitro-etano-diamine. (Machine-translation by Google Translate, not legally binding) |
-
1984
- 1984-05-02 HU HU841690A patent/HU198196B/en not_active IP Right Cessation
-
1985
- 1985-04-29 SU SU853885802A patent/SU1375133A3/en active
- 1985-04-29 MX MX205130A patent/MX161373A/en unknown
- 1985-04-30 CS CS853160A patent/CS259878B2/en unknown
- 1985-04-30 YU YU73385A patent/YU45714B/en unknown
- 1985-04-30 ES ES542782A patent/ES8609292A1/en not_active Expired
- 1985-04-30 NO NO851727A patent/NO168942C/en unknown
- 1985-05-01 KR KR1019850002962A patent/KR920005828B1/en not_active IP Right Cessation
- 1985-05-02 AR AR300258A patent/AR240455A1/en active
- 1985-05-02 IT IT20558/85A patent/IT1200464B/en active
- 1985-05-02 CA CA000480665A patent/CA1268474A/en not_active Expired - Fee Related
- 1985-05-02 AT AT0129585A patent/AT387573B/en not_active IP Right Cessation
- 1985-05-02 PT PT80382A patent/PT80382B/en not_active IP Right Cessation
- 1985-05-02 DK DK196785A patent/DK196785A/en not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| DK196785A (en) | 1985-11-03 |
| CS316085A2 (en) | 1988-03-15 |
| AT387573B (en) | 1989-02-10 |
| IT8520558A0 (en) | 1985-05-02 |
| NO168942B (en) | 1992-01-13 |
| CS259878B2 (en) | 1988-11-15 |
| HUT37774A (en) | 1986-02-28 |
| FI88501C (en) | 1993-05-25 |
| NO168942C (en) | 1992-04-22 |
| HU198196B (en) | 1989-08-28 |
| FI851742A0 (en) | 1985-05-02 |
| ES542782A0 (en) | 1986-08-16 |
| IT1200464B (en) | 1989-01-18 |
| YU45714B (en) | 1992-07-20 |
| FI851742L (en) | 1985-11-03 |
| ES8609292A1 (en) | 1986-08-16 |
| SU1375133A3 (en) | 1988-02-15 |
| PT80382A (en) | 1985-06-01 |
| MX161373A (en) | 1990-09-18 |
| NO851727L (en) | 1985-11-04 |
| GR851062B (en) | 1985-11-25 |
| KR920005828B1 (en) | 1992-07-20 |
| AR240455A1 (en) | 1990-04-30 |
| KR850008671A (en) | 1985-12-21 |
| DK196785D0 (en) | 1985-05-02 |
| YU73385A (en) | 1987-12-31 |
| ATA129585A (en) | 1988-07-15 |
| PT80382B (en) | 1987-08-19 |
| FI88501B (en) | 1993-02-15 |
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