CA1279328C - Process for preparing basic thioethers and the salts thereof - Google Patents
Process for preparing basic thioethers and the salts thereofInfo
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- CA1279328C CA1279328C CA000458870A CA458870A CA1279328C CA 1279328 C CA1279328 C CA 1279328C CA 000458870 A CA000458870 A CA 000458870A CA 458870 A CA458870 A CA 458870A CA 1279328 C CA1279328 C CA 1279328C
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- monohydrochloride
- dihydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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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- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention provides a process for preparing the hydrochloride of 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methylamino-2-nitroethylene of formula (I) and, if desired, for transforming this compound to the base of formula (I), which comprises a) reacting the monohydrochloride of 2-[(2-aminoethyl)-ethiomethyl]-5-dimethylaminomethylfuran of formula (II) with 1-methylthio-1-methylamino-2-nitroethylene of formula (III) optionally in the presence of water and/or of an organic solvent, or b) reacting the hydrochloride of 5-dimethylamino-methy1-2-furfuryl alcohol of formula (IV) with cysteamine hydro-chloride at a temperature between 20 and 120°C without adding a solvent. In the presence of a catalytic amount of a mineral acid, or in the presence of a catalytic amount of a substance furnish-ing a mineral acid, then, if desired, separating the obtained dihydrochloride of the base of formula (II) and/or liberating therefrom the monohydrochloride of the base of formula (II) and reacting optionally without separating it with 1-methylthio-1-methylamino-2-nitroethylene of the formula (III) and, if desired, separating and purifying the hydrochloride of the base of formula (I) and/or, if desired, liberating therefrom the base of formula (I) and/or, if desired, purifying and transforming it to the hydrochloride thereof. The invention also provides as inter-mediates in the process 2-[(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethylfuran dihydrochloride or 2-[(2-aminoethyl)-thiomethyl]
-5-dimethylaminomethylfuran monohydrochloride.
The invention provides a process for preparing the hydrochloride of 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methylamino-2-nitroethylene of formula (I) and, if desired, for transforming this compound to the base of formula (I), which comprises a) reacting the monohydrochloride of 2-[(2-aminoethyl)-ethiomethyl]-5-dimethylaminomethylfuran of formula (II) with 1-methylthio-1-methylamino-2-nitroethylene of formula (III) optionally in the presence of water and/or of an organic solvent, or b) reacting the hydrochloride of 5-dimethylamino-methy1-2-furfuryl alcohol of formula (IV) with cysteamine hydro-chloride at a temperature between 20 and 120°C without adding a solvent. In the presence of a catalytic amount of a mineral acid, or in the presence of a catalytic amount of a substance furnish-ing a mineral acid, then, if desired, separating the obtained dihydrochloride of the base of formula (II) and/or liberating therefrom the monohydrochloride of the base of formula (II) and reacting optionally without separating it with 1-methylthio-1-methylamino-2-nitroethylene of the formula (III) and, if desired, separating and purifying the hydrochloride of the base of formula (I) and/or, if desired, liberating therefrom the base of formula (I) and/or, if desired, purifying and transforming it to the hydrochloride thereof. The invention also provides as inter-mediates in the process 2-[(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethylfuran dihydrochloride or 2-[(2-aminoethyl)-thiomethyl]
-5-dimethylaminomethylfuran monohydrochloride.
Description
1.'~>,~33~
This invention relates to a process for preparing the hydrochloride oE l-~2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]~-amino-l-methylamino-2-nitroethylene of the formula (I) \ N-~12C ~ C112-S-(~ll2)2-~ Nl~ 3 (I) 1~3C C11-~02 and, if desired, for transforming this compound to the base of formula ~I). Ayain, the invention relates to new key intermediates for preparing the above compounds, namely to the new dihydrochloride and monohydrochloride of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran of formula (II) / ~-H2C ~ C112-S-(cII2)2-~ll2 ~II) 1[3C
as well as to a process for the preparation thereof.
Being a selective histamine H-2 receptor antagonist, the compound of formula (I) is an outstanding drug in the treatment of gastric and duodenal ulcers. For therapeutical purposes the hydrochloride of the compound of formula (I) is used.
For preparing the hydrochloride of the compound 3h-~
of formuLa (I), the foLLowing processes are clescribed in the literature.
a) According -to the E~ampLe 32 reported in the published Ge~nan patent application ~o.
_ i 2~734,o70, the hydrochloride of the com-pound of formula (I) is prepared by dis-soLving the base of formuLa (I) in ethanol and precipitating the h~-drochLoride formed by adding ethyl acetate to give a 89.6 do yieLd of the hydrochloride as caLcuLated for the base used as starting ~aterial.
According to the BeLgian patent specification ~o. 890,~74 (page 2, Lines ~ to 7), the h~-drochLoride of t the compound of formula (I) obtained in this ~ay sb~h~
L~ unsuitabLe fiLtering and dr~-in~ characteristics and this process does not have the desirabLe feat~es of a manu-facturing process.
b) Accordin~ to the E~ampLe L of the BeL~ian patent specification No. S90,~74, -the hydro-chLoride of the compound of fo~llula (I) is prepared by adding concen-trated aqueous hydrochLoric acid to a soLu-tion of the base of for~uLa (I) in aqueous isopropanoL soL-ution and precipitating the hydrochLoride 2~ formed by adding a further amount of iso-propanol to give a 93,9 ~ yieLd of the hydrochLoride as caLcuLated for the base.
Thus, the starting materiaL for both processes B
is the base of formula (I). Tllerefore, based on the processes known at presen-t, the base of ~ormula (I) shouLd first be prepared in an appropriate quality for the formation of the hydrochloricle.
Three processes for -the syn-thesis of the base of fo~mula (I) are described in the published German patent application No. 2,734,070 cited above (Examples 1~, 20 and 2L). Out of these, the resuLt given in Example L~ is most acceptable, according to L0 which the base of formuLa (I) is prepared by reacting the base of formula (II) with L-tnethylttlio--l-mothyLamino-2-nitroethyLene of the fo~nuLa (III) 1~ C=CH-~0~ (III) for about 8 hours in the presence of water, The base of formula (I) with a melting point of o9 to 70 C is -0 obtained in a 78 ~o yield as calculated for the compound of formula (II). A considerable deficiency of this de-scription consists in that the exact conditions for the recrystalLization are not gi~en, although they bear a decisive importance both on the yield and quaLi-ty of 2J the base of formula (I)~
While investigating the course of this reaction, it was found that, by foLLowin~ the proce~s described in ExampLe L~ cited above, we eouLd not obtai~ the base of formula ~I) in a quality permitting the preparation of a hydrochloride satisfying the requirements of a technological process at industrial scale and of the production of pharmaceu-tical compositions.
The difficulties connected with the preparation of the base of formula (I) and its hydrochloride, respectively, useful for pharmaceutical preparations as well as the lack of a satisfactory solving of this problem are indicated also by the fact that a number of further patent applications for the preparation of these compounds have been filed, such as the published British patent application No. 2,075,98~ A; the Belgian patent specifications Nos. 886,997 and 890,574; the Spanish patent specifications Nos. 495,493: 497,386; ~97,737;
502,940; 504,461; 507,360; 508,693; 511,830; and 512,315; as well as the published European patenk applications Nos.
55,625; 55,626; 59,082; and 64,869. However, the processes involved in the patent specifications and applications cited above do not give a satisfactory solution to the difficulties connected with the large-scale production of the hydrochloride of the base of formula (I).
Thus, the present invention provides a process for the preparation of the commpound of formula (I) and of its hydrochloride, which makes possible to produce these compounds in a good yield and in a simple way also on an industrial scale.
Now it has been found, unexpectedly, that the ~' ,, 3~
drawbacks mentioned above can be eLiminated by react-ing the monohydrochLoride of the base of formuLa ( instead of the base of formula (II), as staxting ma~
teriaL with the compound of formula (II~). In addit-.ion, it has becn found -tha-t on using the monohydroohloride of tho base of formuLa (II) as starting mate.riaL~ the hydrochLoride of the compouncl of formuLa (I) usefuL
for pharmaceuticaL compositions can directLy be obtained.
This recognition could not be expected for LO severaL reasons. On the one hand, according to the published German patent appLication No. 2,734,070 cited above, the base of formuLa (I) is obtained by reacting the base form of the compound of formuLa (II) Wittl th0 compound of fol~uLa (III). On the other hand, it is L~ ~eLL known that the dispLacement of the methy-Lthio group b~ amines - such as e.g. in the course of the reaction of the base of formuLa (II) ~ith the compound of for-muLa (III) - is in generaL carried out l~ith the amine bases and not with the hydrohaLides thereof ~Houben--WeyL: ~ethoden der Organischen Chemie, Ed. E. MULLer, VoL. IX~ Georg Thieme VerLag, Stuttgart, L9~~ page 7~7 and in particuLar page 7~8; E~ampLes L4a-; reported ln the pubLished German patent appLication ~o. 2,734,070;
ExampLe L reported in the British patent specification 2~ No. 2,038,322]. FinaLLy, on the basis of the processes known in -the prior art it couLd not be e~pected that the reaction of the monohydrochLoride of the baqe of formuLa (II) with the compound of fo.nmuLa (III) wiLL directLy .:
3~
result in the formation of a preferable form of the hyrdrochloride of the compound of formula (I).
The compound of formula (III) used in the process of the invention is known from the literature (published Brltish patent application No. 2,075,960 A, page 3, E~ample l).
The monohydro~hloride of the base of formula (II) used in the process of the invention is a new compound which, before its reaction with the compound of formula (III), can be prepared in a good yield either separately or in situ from the new dihydrochloride of the base of formula (II) or, if desired, from the base of formula (II). The invention also relates to the new hydrochloride salts of the base of formula (II) as well as to the prepartation thereof.
It has been found that these compounds can be prepared very advantageously by reacting the hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of the formula (IV) C ~ C112-011 (IV) with cysteamine hydrochloride.
Thus, the present invention relates to a new process for preparing the hydrochloride of l-~2-[5-dimethylaminomethyl-2-(furylmethythio)-ethyl]~-amino-l--methylamino-2-nitroethylene of formula (I) and, if desired, for transfor~ing this compound to the base of formula (I), which comprises a) reacting the monohydrochLoride oP 2-C(2--aminoethyl)--thiomethyl~-~~dlmethylamino-methylfuran of forrnula (II) wi-th l-methyl-thio-l-methylamino-2-nitroethrlene of ~he formula (III) optionaLly in the presence of water and/or of an organic solvent, or b) reacting the hydrochLoride of` 5-di~ethylamino--methyL-2-furfuryL aLcohol of formuLa (IV) with cysteamine h~drochLoride at a tempera-ture between 20 and 120 C in the absence of any soLvent or, if desired, adding an inert organic diluent, in the presence of a cataLytic a~ount of a mineraL acid and optionaLLy of an organic acid (having a pKa value of 0 to 2), or in the presence of a cataLytic amount of a substance fur-nishing under the above-mentioned conditions a mlneral acid and optionally an organic acid (having a pKa value of 0 to 2), then, if desired, separating the obtained dihydro-chloride of the base of fonmuLa (II) and/or 2~ llberating therefro~ the monohydrochLoride of the base of formuLa (II) and reacting it, optionalLy without separation, with l-methyl-thiG-L-methylamino-2-nitroethylene o~ the for~ula (III) : , ' : ~
and, if desired, separating and puri~yin~ the hydro-chLoride of the base of formuLa (I) prepared by the process a) or b) and/or, if desired, Liberating there-from the base of for~uLa (I) and/or, if desired, purify-ing and transforming i-t to the hydroohLoride thereo~, A preferrod embodiment of prooess a) of -the invention oomprises reaoting the hydrochLoride of the base of formuLa (II) prepared separateLy with the com-pound of formula (III) at a temperature between 20 and L0 90 C. ALternativeLy, the monohydrochLoride of the base of formuLa (II) may be formed in situ from the dihydro-chLoride of the base of formuLa (II) suitabLy by neu-traLizing one moLecuLa hydrogen chLoride present in the dihydrochLoride with an aLkaLine agent, prcferabLy by L~ using an aLkaLine rnetaL hydrogen carbonate, aLkaline metaL carbonate or hydro~ide or an appropriate organic base and the monohydrochLoride obtained in situ is reacted with the co~pound of formula (III). ~he process a) of the invention may preferabLy be performed in the presence of water and/or o~ an organic solvent, e.g.
methanoL.
A preferred embodiment of process b) of the invention comprises reacting the hydrochLoride of the compound of formuLa (IV) with cysteamine hydrochL~ride 2~ in the presence o~ a cataLytic amount of a mineraL acid, preferably of hydrochLoric acid, without adding a soLvent, if desired, in the presence of an inert oreanic diluent, optionaLLy by using miLd vacuum. This reaction is carried 3~;~
g out at a temperature between 20 and L20 C~ preferabLy between 20 and 7~ ~C. A part of the cataLytio ~mount of the mineraL acid may be substituted by an organLc acid of a similar strength (pKa ~aLue of 0 -to 2), prefer-abLy by a sulphonic acid, e ~ by p--toluenesulphonlo acid.
The dihydrochLoride salt formed accordin~ to the process o~ the invention may be separated in a known manner, e g~ by adding a Lower aLkanoL, e.g.
L0 ethanoL or a mi~ture of a Lower aLkanoL with a Lower aLiphatic ketonet e.~. acetone, to the cooLed reaction mi~ture, ~hereby the dihydrochLoride of the base of for-muLa (II) is precipi~ated mostLy in a crystaLLine form and can be separated by fiLtration.
L~ In this war, the dihydrochLoride of the base of formuLa ~II) can be obtained e.g. in a 87 ~O yieLd.
The free base of for~uLa (II) can be Liberated from its dihydrochloride obtained in the above-mentioned reaction either in situ or after separating the dihydro-chLoride, by addin~ an appropriate basic substance,e,~, an alkaLine metaL hydro~ide, to the dihydrochLoride.
From this base the monohydrochloride can be formed in a manner known in the art. ALternativeLy, ho~ever, the dihydrochLoride saLt of the base of formuLa (II) obtained 2~ by the process of the inYentiOn may directLy be trans-formed to the monohydrochlorids of the ba e of fo~uLa (II) without Liberating the base~ From the monohydro-chLoride obtained in thi~ way, the hydrochLoride of - : , ~:' 9~
1-{2~[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl])--amino-1-methylamino-2-nitroethylene of formula (I) can directly be prepared according to process a).
Another preferred embodiment of process b) of khe invention comprises adding to the mixture containiny the hydrochloride of the compound of formula (IV) and cysteamlne hydrochloride a catalytic amount of a substance furnishing under the reaction conditions a mineral acid or a mineral acid and an organic acid having a similar strength to that of the mineral acids, preferably a phosphorus halide (e.g.
phosphorus oxychloride) or an organic or an inorganic acid halide (e.g. thionyl chloride, p-toluenesulphonyl chloride) or aluminium chloride, then reacting the components at a temperature between 50 to 90 C, in the absence of any solvent for 2 to 3 hours. In this way, the dihydrochloride of the base of formula (II) can be obtained in a 82 to 92 %
yield.
According to the process b) of the invention, if desired, the hydrochloride salt of the compound of formula (IV) can be fused with cysteamine hydrochloride in the presence of an inert organic diluent whi~h does not dissolve any of the starting hydrochlorides. The use of such diluents can be particularly advantageous when the process of the invention is used for a large-scale production. Aliphatic, aromatic or halogenated aliphatic hydrocarbons may suitably be employed as diluents. Preferably benzene, toluene, dichloroethane or petroleum ether (with a boiling point of 60 to 100C) - lL -nay be used as diluents for this fusion reaction.
From the dihydrochloride of the base of formula (II) obtained in this way, the monohydrochLoride o~ the base of formula (II) can be prepared ancl reaoted with L-methyLthio-L-me-thylamino-2-nitroethylene of the formuLa (III) in the manner mentioned above.
The reaction mi~ture, obtained as a result of the process of the invention, essentiaLLy contains the hydrochLoride of the base of for~uLa (I), t~hich crystaLLizes out from the mi~ture opti~naLLy after adding an appropriate solvent or soLvent mi~ture, e,g, aqueous ethanoL or a mi~ture of ethQnoL with acetone to the reaction mi~ture, The puri-ty of the h~drochLoride of the base of formula (I) obtained in the reaction of the in~-ention is at Least of 9~ ,~o. If desire~, this product may further be purified by using chromatography ancl~or fractional crystaLlization.
The hydrochLoricle of 5-dimethyLaminotnethyL-2--f~rfur~L aLcohoL of the formuLa (IV) used in process b) of the invcntion is a known substance ~J. .-~m. Chem, Soc, 69, 4S4 (L947)~, The cysteamine h~drochloride is commerciaLLy avaiLabLe, The advantages of the process of the invention can be summarized as foLLows, When the direct aim is to prepare -the hydro-chLoride of the base of for~ula (I), it is not inevitabLy needed to prepare and separate the base of formuLa (I) 7~
in a separate step for forming the hydrochLoride. ~his is particularly advantageous, as the preparation of the base of formuLa O in a pure, crystaLLine f~ m according to the prior art is probLematio.
By using -the process of the invention, the hydrochLoride of the base of formuLa (I) is directl~ ob-tainecl in an advantageous cr~-stalLine form~.
The voLume demand of the process of the inven-tion is ver~ Low~ as no separate addition of any soLvent to the react~nts is needed.
Basecd on these facts, the process of the inven-tion is useful for the simple preparation of the base of formula (I) arld its h~drochLoride in a good yieLc] at Qtl indùstriaL scale, too.
The nel~ dihydrochLoride saLt of the base of formuLa (~) prepared accorcling to the process of the invention is a weLL-defined, stabLe compound that can be stored ~rithout aLteration and from ~hich, if desired, the base of formula (II) or the ne~ monoh~drochLoricle saLt thereof can be prepared at any time, suitabLy shortLy before the use.
The process of the invention is iLLustrated in cletaiL by the foLLowing non-Limiting e~ampLes.
Example L
Preparation of 2 [(2-aminoethyL)-thiomethyL]--~-dimeth~Laminomethylfuran dihydrochLoride [dihydrochLoride of the ba~e of formuLa (~) -A mixture containing cysteamine hydrochloride (9.08 g, 0.08 mole) and 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (15.32 g, 0.08 mole) is fused while stirring at 70 to 75 C, then concentrated hydrochloric acicl ~0.75 ml) is added and the mixture is stirred further at 80 C for one hour and at 90 C for 20 minutes under mildly reduced pressure (40 to 60 KPa). After cooling to 70 C, abs.
ethanol (15 ml~ is added and the reaction mixture is kept at room temperature for 2 hours, then abs. acetone (15 ml) is added, the mixture is kept at 0 to 4 C overnight, the crystalline precipiatate is filtered, washed and a 1:1 mixture of ethanol and acetone and dried to give 20.19 g (87.2~) of the aimed product, m.p. 160 to 162 C.
Example 2 Preparation of 2-[(2-paminoethyl~-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride. A mixture containing cysteamine hydrochloride (14.7 g, 0.13 mole), 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (23.0 g, 0.12 mole) and concentrated hydrochloric acid (5 ml) is heated to 60 C under stirring within a few minutes. After about 10 minutes, a melt is formed which is let to cool to room temperature, stirred at room temperature for 6 hours and set aside at room temperature for 60 hours. The crystalline mixture is suspended in ethanol (100 ml), dissolved hy heating to the boiling point, cooled rapidly while stirring, kept 7~3'~
at 0 to 5 C for one hour, filtered, ~iashed with iee--coLd ethanoL anc~ dried to give 25 g (72.5 ~0) of the aimed produet, m.p, 163 to L65 C after ree~ystaLlization from 96 $ ethanol, E~ample 3 Preparation of 2-C(2-aminoethyL)-thiomethyLj--5-dimethylaminomethylfuran dihydrochLoride A mi~ture eontaining cysteamine hydrochLoride L0 (L9.0 g, o.L67 moLe) and ~-dimethyLaminomethyL-2-furfur~L
aLcohoL hydrochLoride (32.0 D~ o,L6'3 moLe) is fused at 67 C, then eoncentrated hydrochLoric acid (L.0 ml) is added. The temperature is increased t~ 90 C ~ithin 16 rninutes, a fur-ther amount of concentrated hydroehLoric L5 acid (0.5 mL) is added, the mi~ture is stirred at this temperature for 40 minutes, cooLed to 80 C and abs, ethanol (9~ ml) is added, The cr~-stalline mi~ture is thoroughly stirred, eooled, filtered, ~iashed ~ith abs, ethanoL and dried to gi~e 40r L g (83.7 ~o as ealeulated for e~-ste~mine hydroehloride) of the aimed procluet, m.p. L59 to L61 C.
E~ampLe 4 Preparation of 2-[(2-aminoethyL)-thiomethyl~-2~ -~-dimethylaminomethyLfuran dihydrochLoride A mixture eontaining eysteamine hydroehloride (29.4 g, 0.26 moLe) and 5-dimethyLaminomethyL-2-furfuryl aLeohoL hydroehLoride ~45.96 g, o,24 moLe) is meLted - L~ -while stirring in a water bath kep-t at 70 to 7~ C.
After reaching an internal temperat~e of 60 a (about 30 minutes), concentrated hydrochLoric acid (3.6 mL) i9 added dropwise within L0 minutes, -then t~e mi~-ture 5 is stirred at 60 C for 3 hours and at 70 C Por L ho~, Abs. ethanol (60 mL) is added, then the mi~ture is Let to cool ~o 40 oc~ ace-tone (60 ml) is adcled, s-tirred for 2 hours at room temperature and then kept at ~ to L0 C
overnigh-t. The crystaLs precipitated are colLeoted, L0 washed with ethanoL and acetona and clried in the air to gi~-e ~.4 g (80.4 ~) of the aimed product, m.p. L~8 to L60 C.
E~am~Le ~
L~ Prcparation of 2-[(2-aminoethyL)-thiomethyl]--~-dimethyLaminomethyLfuran dih~drochLoride A mi~ture containing cysteamine hydrochLoride (9.08 g, 0.08 moLe), ~-dimethyLaminomethyL-2-furfuryL
aLcohoL h~-drochLoride (L~.32 g, 0.08 moLe) arld water (L
mL) is heated to 30 C under stirring to give a homogeneous melt, then concentrated hydrochLoric acid (o.6 mL) and a soLution of ethyL chLorosuLphite (0.~ mL, prepared in the manner cl~scribed beLow) are ~dded ~ithin L0 minute9, whereupon the mi~ture is stirred at 60 C for 3 hours, 2~ and at 70 C for one hour. Abs. ethanoL (20 mL) is added, then the mi~ture is Let to cooL to 40 C~ aeetone (20 mL) is added, stirred at room -temperature for 2 hours and kept at ~ to L0 C overnight. Thereafter, the process described 3~3~
- L6 _ in ExampLe 4 is followed to give 19.48 ~ (84.8 ~) of the aimed product, m.p. 158 to 160 C.
~ he solution o~ ethyL chLorosuLphite is pre~
pared by dropping -thion~L chLoride (2.8 mL) -to abs.
ethanoL (10 ~1) kept at -20 C, then stirring the soL-ution at -L0 C for 30 minutes.
ExampLe 6 Preparation of 2-C(2-aminoethyl)-thiomethyL~--5-dimethyLaminomethylfuran dihydrochLoride A mixture containityg cysteamine hydrochloride (4.~4 g~ 0.04 moLe) and 5-dimethyl~ninolnethyl-2-furfuryL
alcohol hydrochLoride (7.66 g~ 0.04 mole) is fused at 70 to 7~ C ~hiLe stirring) concentrated hydrochLoric acid (O.L8 ml) is added~ heated to 80 C, p-toLuenesul-phonic acid (0.~ g) is added, then stir~ed at 80 C for one hour and at 90 C for 20 minutes under miLdLy re-duced pressure (40 to 60 KPa). Aft~r cooLing down, the reaction mixture is worked up as described in ExampLe L
to give 9.83 g (85.4 ~) of the aimed product, m.p. 1~8 to L60 C.
Exa~ple 7 Preparation of 2-[(2-aminoethyL)-thl~methyl~--5-dimethylaminomethylfuran dihydroch]oride The prooe3~ described in Example 6 i9. foLLowed, except that 8~ ~ phosphorio acid (0 3 ml) i9 used instead of p_toluenesuLphonic acid to give 9.8 g (8~.3 ~) of the .
-~3 1~7 aimed product, m.p. L58 to 160 C.
E~ample 8 PreParatiOn of 2-[(2-aminoethyL) thiom0thyL~--3-dimethyLaminomethyLfuran dihyclrochLoride A mixture containing cysteamine hydrochluride (9.08 ~, 0.08 moLe)and 3-dime~hylaminomethyL-2-furfuryl aLcohoL hydrochLoride (L3.32 g, 0.08 mole) is fused at 78 C, thionyL chLoride (0.2 m~) is added, and stirred ~o at 80 C for L0 minute~, then at 80 C for 30 minutes and at 90 C for 20 minutes under miLdLy reduced pressure, After cooLing to 70 C, abs. ethanoL (20 mL) is added, heated to boiLin~, a further amount of abs. ethanoL
(20 mL) and acetone (40 mL) are added, and kept at ~ C
L~ overni~ht. The crystaLLine precipitate is washed with a L:l mi~ture of ethanoL and acetone and dried to give L9,6 g (8~.3 ~0) of -the aimed product, m.p. L~6 -to L38 C.
E~ampLe g .
Preparation of 2-[(2-aminoethyL)~thiomethyL~--~-dimethylaminomethyLfuran dihydrochloride The process described in E~ample 8 is ~ollowed, except that aLuminium chLoride (L g) is used, instead of thionyL chLoride, to ~ive 2L.1 g (9L.9 ~) of the aimed 23 product.
E~ampLe L0 Preparation of 2-~(2-aminoethy-L~-thiomethyL]-:1~ 7~3~B
-~-di~ethylaminomethylfuran dihydrochloride An intimate mixture containing ~-dimethyLamino-methyL-2-furfuryl alcohol hydrochLoride (9~ 7~ g, 0.~
moLe), cysteamine hydrochLoride of 9Z % (64 g, 0.~2 moLe) and concentrated hydrochLoric acid (9.3 mL) i~ stirred in the presence of benæene (2~0 mL) at 60 to 62 C for 4 hours The benzene is decanted, the residue is stirred with abs. ethanoL (23~ ml) in a water bath of 80 C for some minutes, then acetone (23~ mL) i9 added, the mi~ture L0 is stirred and then kept at 0 to 4 C overnight. The crystaLLine precipitate is fiLtered, washed and dried to ~ive 124.5 ~ (86.7 ~) of the aimed product, m.p~
L6L to L64 C.
Whan 3.8 g of this prod~ct is recr~staLLi~ed L5 from ethanol (6 mL) and while cooLing acetone (6 mL) is added, 3.59 g of an anaLytical specimen are obtained, ~,p. L63 to 166 C.
ExampLe Ll Preparation of 2-~(2-aminoethyl)-thiornethyl~_ -S-dimethyLaminomethylfuran dihydrochLoride The proces~ described in ExampLe 10 is folLowed, except that, instead of benzene~ dichloroethane is used a~ diluent, with stirring at the boiling point for 3.~
2~ hours. The aimed product i9 obtained in a yield of 89 ~0, m.p L~7 to 16L C.
3X~
,9 E.Yample L2 Preparation of 2-[(2-aminoethyl)-thiomethyL~--~-dimethylaminomethylfuran dih~rclrochloride The process described in E~ampLe L0 is f'olLo~ed, 5 e~ccept that~ instead o~ benzone, petroleum ethor (with a boiLing point oP 70 to 80 C) Ls used as a cliLuent.
Tha aimed product i~ obtained in a 83 ~0 yield, m.p.
160 to L62 a.
E~cample L3 Preparation of 2-[(2-aminoethyL)-thiomethyL~--5~dimethylaminomethyLfuran base [base of the formuLa (II)~ from its dihydrochLoride To a mixture containing 2-C(2-aminoethyl)-15 -thiomethyl~ dimethy~aminomethylfuran dihydrochloride (38.6 g, 0.134 mole) and water (19 ml), sodium hydro}~ide solution of 40 aJ0 (29 ml) is added and the base is e~ctract~
ed into ethyL acetate (3 times 30 ml). rhe organic Layers are combined, dried o~er anhydrous potassiw~ carbonate, 20 filtered, the solvent is evaporated and the residue is distilLed under reduced pressure b~ using a Vigrewc dephLegmator. The aimed product is obtained in a ~ieLd of 22.8~ g (79.4 ~), b.p. L16 to 120 C/L3.3 Pa.
ExampLe 14 Preparation o~' 2-[(2-aminoethyL)-thiomethyL]--~-dimethylaminomethyLfuran monohydrDchLoride [monohydrochloride of the base o for~ula (II)]
3~
_ 20 -rO a suspension containin~ 2-C(2-aminoethyl)--thiomethyL~-5-dimethyLaminomethyLfuran dihydrochLoride ~2.87 g, O.OL moLe) in abs. ethanoL (25 mL)~ a soLution of potassium hydrogen carbona-te (1.0 g, O.OL mol0) -ln water (4 ml) is added under stirrLng a-t 20 C. The ml~-ture is stirred for 30 minutes, the precipitated potas3ium chLoride i9 fiL-tered and the solution evap?rated to dry-ness, The residue is triturated with ether, fiLtered, washed with ether and dried to give 2.42 g (96 ~) of the L0 aimed product, m.p, L15 to LL6 C.
E~ample L~
Preparation ~f 2-C(2-aminoethyL)-thiomethyL~--~-dimethyLaminomethyLfuran monohydrochloride A solu-tion of 2-~(2-c~ninoethyl)-thiomethyL~--5-dimethyLaminomethylfuran base ~2L.4 g, O.L moLe) in methanol (50 ml) is added dropwise to the soLution of 2-~(2-aminoethyl)-thiomethyL]-5-dimethyLaminomethyLfuran dihydrochLoride (28.7 ~, O.L moLe) in methanoL ~300 mL), then the mixture is stirred for ten minutes and then evaporated to dryness under reduced pressure, The residue i9 triturated with ether (100 mL)~ kept at 0 to 4 C for 2 hours, fiLtered, washed with ether and dried at 20 C
to give 48 g (89 %) of the aimed product, m.p. llL to 112 C.
Example 16 Preparation of 1-~2-[t-dimethylamminomethyl-2-(furylmethylthio)-ethyl))-amino-l-methylamino-2-nitroethylene hydrochloride [hydrochloride of the base of formula (I)]
A mixture containing 2-[(2-aminoethyl)-thiomekhyl]-5-dimethylaminomethylfuran monohydrochloride (12.54 g, 0.05 mole), l-methylthio-l-methylamino-2-nitroethylene (7.41 g, 0.05 mole) and water t2.5 ml) is fused at 70 to 75 C with stirring for 2 hours. Gas evolution is observed. After cooling, the reaction mixture is dissolved in ethanol (70 ml), clarified first by activated charcoal, then by Hyflo, the pH value of the filtered solution is adjusted to 5 by co~centrated aqueous hydrochloric acid, cooled to O C, inoculated and stirred at O C for some hours, then kept at O
to 4 C overnight. The precipitate is filtered, washed with abs. ethanol and dried at 50 C under reduced pressure to give 6.1 g (34.8 ~) of the aimed product, m.p. 139 to 141 C.
From the mother liquor, an additional amount of 3.8 g (21.7 ~) the aimed product of similar guality is obtained, m.p. 139 to 141 C.
Example 17 Preparation of 1-(2-[5-dimethylaminomethyl-2-(furylme-thylthio)-ethyl])-ammino-l-methylamino-2-nitroethylene hydrochloride A solution of postassium hydrogen carbonate _ ~2 -(1.0 g, 0.01 m3Le) in water (4 rnL) i9 added to 2-C(2--~minoethyl)-thionnethyL~-3-dimethyLaminomethyLfuran dihydrochLoride (2.87 g, 0.0] moLe). After stirrin~ for 10 minutes, l-me-thyLthio-L-methylamino-2 nitroethyLene (L.~2 g, O.OL02 moLe) is added~ the mi~ture is stirred at 40 to 30 C for L ho~r, heated to 60 C within lV
minutes, stirred at 60 C for L hour and at 70 C for 30 minutes. After cooling, abs. ethanol (30 mL) is added, the precipitated potassi~un chLoride is fiLtered out and the fiLtrate is e~aporated to dryness ~nder reduced press~e. rhe resid~le is clissoLved in 96 ,~o e-thanoL (L3.8 mL), the pH vaLue of the soLution is ~djusted to 5.5 to 6 by adding a fe~ drops of aqueous conc~nt~ated tlyCI~O-chLoric acid, stirred at 0 C for 3 hours nnd ~ept at 0 to 4 C overnight. The precipitate is fiLtered and treatecl as described in E~ampLe L6 to gi~e L.~7 g (~0.5 '~0) of the aimed product, m.p, L38 to L40 C.
From -the mother Liq~or an additionaL amount of O.L9 g (3.4 ~ of the aimed prod~lct is obtained, m.p. L38 to L40 C.
E~lpLe L8 Preparation of L-~2-~3-dimethyLaminollleth~L-2--(fur~LmethyLthio)-ethyL~?-amino-l-meth3rLatnino--2-nitroethyLene hydrochLoride A solution of potassi~n hydrogen carbonate (5.0 g, 0.03 moLe) in water (20 ml) is added to 2-~(2--aminoethyL)-thiomethyL]-3-dimethyLaminomethyL~ran .
~'~7~3~3~
- 2~ -dihydrochlor~de (L4~3S g, O.OS moLe). After stirring for L0 minutes, ].-methyLthio-L-methyLamino-2-nitro-ethylena (7~4~ g, 0.0~ ~ol0) is added, the mixture is ~tirred at 40 to S C for one hour, heated to 60 a within L0 minutes, stirrod at 60 C for one hour and at 70 C for 30 minute~. ~hereafter, the reaction mixture i9 diLuted with water (30 ml)~ the pH vaLue pf the soL-ution is adjusted to 5 by adding 2N aqueous hydrochLoric acid and extracted with chLorofor~ (2 times 30 mL). The pH ~aLue of the aqueous Layer is adjusted to L0 by usin~
2N aqueous potassium hydroxide soLution and extracted into chLorofor~ (four times 30 ml). The combined organic phase is dried over anhydrous sodiwm suLphate and evap-orated to dryness under reduced pressu~-e. ~he residue is dissoLved in abs. ethanoL (70 mL) and clarified by usin~
at first activated charcoal and then Hy-fLo. Aqueous concentrated hydrochLoric acid i9 added dropwise to the fiLtrate in order to adjust the pH ~aLue -to ~ S to 6, then the mixture is stirred (optionaLLy after inocuLation) at 0 C for 3 hours and kept at 0 to 4 C o~ernight. The precipitate is fiLtered and treated as described in Example 16 t~ gi~e 7.1 g (39 ~) of the aimed product, .p. 139 to 141 C.
From -the mother Liquor an additional amount of 3.~ g (L9 ~) of the aimed product i~ obtained, m.p~
L39 to L4L C.
93~
Example 19 Preparation of 1-(2-[5-dimethylaminomethyl-2-tfurylme-thylthio)-ethyl])-amino-1-methylamino-2-nitroethylene hydrochloride-2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran monohydrochloride prepared in situ in an amount of 0.01 mole as described in Example 17 is mixed with 1-methylthio-l-methylamino-2-nitroethylene (1.48 g, 0.01 mole) and stirred at room temperature for 8 hours, kept at room temperature for 14 hours and then stirred at the same temperature for one hour. Water (40 ml) is added, the pH
value of the solution is adjusted to 5 by adding 2N
hydrochloric acid, the mixture is extracted with chloroform (3 times 10 ml~, then the pH value of the a~ueous phase is adjusted to 10 by adding 2N aqueous potassium hydroxide solution and extracted into chloroform (4 times 20 ml~. The combined organic phase is dried and evaporated under reduced pressure. The remained crude base is dissolved in abs.
ethanol (4 volumes), clarified and filtered. The pH value of the ethanolic solution is adjusted to 5 by adding aqueous concentrated hydrochloric acid at 0 C. THe solution is inoculated, stirred at 0 C for 3 hours and kept at 0 to 4 C
overnight. The precipitate is filtered, washed with ethanol and dried to give 1.05 g ~29.9 %) of the aimed product, m.p.
13g to 141 C.
From the mother liquor, Q.9 g (26 %) of the aimed product is isolated, m.p. 138 to 140 C.
s~3~3~
- 2~ -F~onl the crude base of fonnula (I) obtained in the course of the working-up procedure, a crystaLline product can be obtained in a known manner, e.~. b~ re-crystaLLization froln 4-methyl-2-pentanone~ In~p- 67 ~o 6~ C.
This invention relates to a process for preparing the hydrochloride oE l-~2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]~-amino-l-methylamino-2-nitroethylene of the formula (I) \ N-~12C ~ C112-S-(~ll2)2-~ Nl~ 3 (I) 1~3C C11-~02 and, if desired, for transforming this compound to the base of formula ~I). Ayain, the invention relates to new key intermediates for preparing the above compounds, namely to the new dihydrochloride and monohydrochloride of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran of formula (II) / ~-H2C ~ C112-S-(cII2)2-~ll2 ~II) 1[3C
as well as to a process for the preparation thereof.
Being a selective histamine H-2 receptor antagonist, the compound of formula (I) is an outstanding drug in the treatment of gastric and duodenal ulcers. For therapeutical purposes the hydrochloride of the compound of formula (I) is used.
For preparing the hydrochloride of the compound 3h-~
of formuLa (I), the foLLowing processes are clescribed in the literature.
a) According -to the E~ampLe 32 reported in the published Ge~nan patent application ~o.
_ i 2~734,o70, the hydrochloride of the com-pound of formula (I) is prepared by dis-soLving the base of formuLa (I) in ethanol and precipitating the h~-drochLoride formed by adding ethyl acetate to give a 89.6 do yieLd of the hydrochloride as caLcuLated for the base used as starting ~aterial.
According to the BeLgian patent specification ~o. 890,~74 (page 2, Lines ~ to 7), the h~-drochLoride of t the compound of formula (I) obtained in this ~ay sb~h~
L~ unsuitabLe fiLtering and dr~-in~ characteristics and this process does not have the desirabLe feat~es of a manu-facturing process.
b) Accordin~ to the E~ampLe L of the BeL~ian patent specification No. S90,~74, -the hydro-chLoride of the compound of fo~llula (I) is prepared by adding concen-trated aqueous hydrochLoric acid to a soLu-tion of the base of for~uLa (I) in aqueous isopropanoL soL-ution and precipitating the hydrochLoride 2~ formed by adding a further amount of iso-propanol to give a 93,9 ~ yieLd of the hydrochLoride as caLcuLated for the base.
Thus, the starting materiaL for both processes B
is the base of formula (I). Tllerefore, based on the processes known at presen-t, the base of ~ormula (I) shouLd first be prepared in an appropriate quality for the formation of the hydrochloricle.
Three processes for -the syn-thesis of the base of fo~mula (I) are described in the published German patent application No. 2,734,070 cited above (Examples 1~, 20 and 2L). Out of these, the resuLt given in Example L~ is most acceptable, according to L0 which the base of formuLa (I) is prepared by reacting the base of formula (II) with L-tnethylttlio--l-mothyLamino-2-nitroethyLene of the fo~nuLa (III) 1~ C=CH-~0~ (III) for about 8 hours in the presence of water, The base of formula (I) with a melting point of o9 to 70 C is -0 obtained in a 78 ~o yield as calculated for the compound of formula (II). A considerable deficiency of this de-scription consists in that the exact conditions for the recrystalLization are not gi~en, although they bear a decisive importance both on the yield and quaLi-ty of 2J the base of formula (I)~
While investigating the course of this reaction, it was found that, by foLLowin~ the proce~s described in ExampLe L~ cited above, we eouLd not obtai~ the base of formula ~I) in a quality permitting the preparation of a hydrochloride satisfying the requirements of a technological process at industrial scale and of the production of pharmaceu-tical compositions.
The difficulties connected with the preparation of the base of formula (I) and its hydrochloride, respectively, useful for pharmaceutical preparations as well as the lack of a satisfactory solving of this problem are indicated also by the fact that a number of further patent applications for the preparation of these compounds have been filed, such as the published British patent application No. 2,075,98~ A; the Belgian patent specifications Nos. 886,997 and 890,574; the Spanish patent specifications Nos. 495,493: 497,386; ~97,737;
502,940; 504,461; 507,360; 508,693; 511,830; and 512,315; as well as the published European patenk applications Nos.
55,625; 55,626; 59,082; and 64,869. However, the processes involved in the patent specifications and applications cited above do not give a satisfactory solution to the difficulties connected with the large-scale production of the hydrochloride of the base of formula (I).
Thus, the present invention provides a process for the preparation of the commpound of formula (I) and of its hydrochloride, which makes possible to produce these compounds in a good yield and in a simple way also on an industrial scale.
Now it has been found, unexpectedly, that the ~' ,, 3~
drawbacks mentioned above can be eLiminated by react-ing the monohydrochLoride of the base of formuLa ( instead of the base of formula (II), as staxting ma~
teriaL with the compound of formula (II~). In addit-.ion, it has becn found -tha-t on using the monohydroohloride of tho base of formuLa (II) as starting mate.riaL~ the hydrochLoride of the compouncl of formuLa (I) usefuL
for pharmaceuticaL compositions can directLy be obtained.
This recognition could not be expected for LO severaL reasons. On the one hand, according to the published German patent appLication No. 2,734,070 cited above, the base of formuLa (I) is obtained by reacting the base form of the compound of formuLa (II) Wittl th0 compound of fol~uLa (III). On the other hand, it is L~ ~eLL known that the dispLacement of the methy-Lthio group b~ amines - such as e.g. in the course of the reaction of the base of formuLa (II) ~ith the compound of for-muLa (III) - is in generaL carried out l~ith the amine bases and not with the hydrohaLides thereof ~Houben--WeyL: ~ethoden der Organischen Chemie, Ed. E. MULLer, VoL. IX~ Georg Thieme VerLag, Stuttgart, L9~~ page 7~7 and in particuLar page 7~8; E~ampLes L4a-; reported ln the pubLished German patent appLication ~o. 2,734,070;
ExampLe L reported in the British patent specification 2~ No. 2,038,322]. FinaLLy, on the basis of the processes known in -the prior art it couLd not be e~pected that the reaction of the monohydrochLoride of the baqe of formuLa (II) with the compound of fo.nmuLa (III) wiLL directLy .:
3~
result in the formation of a preferable form of the hyrdrochloride of the compound of formula (I).
The compound of formula (III) used in the process of the invention is known from the literature (published Brltish patent application No. 2,075,960 A, page 3, E~ample l).
The monohydro~hloride of the base of formula (II) used in the process of the invention is a new compound which, before its reaction with the compound of formula (III), can be prepared in a good yield either separately or in situ from the new dihydrochloride of the base of formula (II) or, if desired, from the base of formula (II). The invention also relates to the new hydrochloride salts of the base of formula (II) as well as to the prepartation thereof.
It has been found that these compounds can be prepared very advantageously by reacting the hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of the formula (IV) C ~ C112-011 (IV) with cysteamine hydrochloride.
Thus, the present invention relates to a new process for preparing the hydrochloride of l-~2-[5-dimethylaminomethyl-2-(furylmethythio)-ethyl]~-amino-l--methylamino-2-nitroethylene of formula (I) and, if desired, for transfor~ing this compound to the base of formula (I), which comprises a) reacting the monohydrochLoride oP 2-C(2--aminoethyl)--thiomethyl~-~~dlmethylamino-methylfuran of forrnula (II) wi-th l-methyl-thio-l-methylamino-2-nitroethrlene of ~he formula (III) optionaLly in the presence of water and/or of an organic solvent, or b) reacting the hydrochLoride of` 5-di~ethylamino--methyL-2-furfuryL aLcohol of formuLa (IV) with cysteamine h~drochLoride at a tempera-ture between 20 and 120 C in the absence of any soLvent or, if desired, adding an inert organic diluent, in the presence of a cataLytic a~ount of a mineraL acid and optionaLLy of an organic acid (having a pKa value of 0 to 2), or in the presence of a cataLytic amount of a substance fur-nishing under the above-mentioned conditions a mlneral acid and optionally an organic acid (having a pKa value of 0 to 2), then, if desired, separating the obtained dihydro-chloride of the base of fonmuLa (II) and/or 2~ llberating therefro~ the monohydrochLoride of the base of formuLa (II) and reacting it, optionalLy without separation, with l-methyl-thiG-L-methylamino-2-nitroethylene o~ the for~ula (III) : , ' : ~
and, if desired, separating and puri~yin~ the hydro-chLoride of the base of formuLa (I) prepared by the process a) or b) and/or, if desired, Liberating there-from the base of for~uLa (I) and/or, if desired, purify-ing and transforming i-t to the hydroohLoride thereo~, A preferrod embodiment of prooess a) of -the invention oomprises reaoting the hydrochLoride of the base of formuLa (II) prepared separateLy with the com-pound of formula (III) at a temperature between 20 and L0 90 C. ALternativeLy, the monohydrochLoride of the base of formuLa (II) may be formed in situ from the dihydro-chLoride of the base of formuLa (II) suitabLy by neu-traLizing one moLecuLa hydrogen chLoride present in the dihydrochLoride with an aLkaLine agent, prcferabLy by L~ using an aLkaLine rnetaL hydrogen carbonate, aLkaline metaL carbonate or hydro~ide or an appropriate organic base and the monohydrochLoride obtained in situ is reacted with the co~pound of formula (III). ~he process a) of the invention may preferabLy be performed in the presence of water and/or o~ an organic solvent, e.g.
methanoL.
A preferred embodiment of process b) of the invention comprises reacting the hydrochLoride of the compound of formuLa (IV) with cysteamine hydrochL~ride 2~ in the presence o~ a cataLytic amount of a mineraL acid, preferably of hydrochLoric acid, without adding a soLvent, if desired, in the presence of an inert oreanic diluent, optionaLLy by using miLd vacuum. This reaction is carried 3~;~
g out at a temperature between 20 and L20 C~ preferabLy between 20 and 7~ ~C. A part of the cataLytio ~mount of the mineraL acid may be substituted by an organLc acid of a similar strength (pKa ~aLue of 0 -to 2), prefer-abLy by a sulphonic acid, e ~ by p--toluenesulphonlo acid.
The dihydrochLoride salt formed accordin~ to the process o~ the invention may be separated in a known manner, e g~ by adding a Lower aLkanoL, e.g.
L0 ethanoL or a mi~ture of a Lower aLkanoL with a Lower aLiphatic ketonet e.~. acetone, to the cooLed reaction mi~ture, ~hereby the dihydrochLoride of the base of for-muLa (II) is precipi~ated mostLy in a crystaLLine form and can be separated by fiLtration.
L~ In this war, the dihydrochLoride of the base of formuLa ~II) can be obtained e.g. in a 87 ~O yieLd.
The free base of for~uLa (II) can be Liberated from its dihydrochloride obtained in the above-mentioned reaction either in situ or after separating the dihydro-chLoride, by addin~ an appropriate basic substance,e,~, an alkaLine metaL hydro~ide, to the dihydrochLoride.
From this base the monohydrochloride can be formed in a manner known in the art. ALternativeLy, ho~ever, the dihydrochLoride saLt of the base of formuLa (II) obtained 2~ by the process of the inYentiOn may directLy be trans-formed to the monohydrochlorids of the ba e of fo~uLa (II) without Liberating the base~ From the monohydro-chLoride obtained in thi~ way, the hydrochLoride of - : , ~:' 9~
1-{2~[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl])--amino-1-methylamino-2-nitroethylene of formula (I) can directly be prepared according to process a).
Another preferred embodiment of process b) of khe invention comprises adding to the mixture containiny the hydrochloride of the compound of formula (IV) and cysteamlne hydrochloride a catalytic amount of a substance furnishing under the reaction conditions a mineral acid or a mineral acid and an organic acid having a similar strength to that of the mineral acids, preferably a phosphorus halide (e.g.
phosphorus oxychloride) or an organic or an inorganic acid halide (e.g. thionyl chloride, p-toluenesulphonyl chloride) or aluminium chloride, then reacting the components at a temperature between 50 to 90 C, in the absence of any solvent for 2 to 3 hours. In this way, the dihydrochloride of the base of formula (II) can be obtained in a 82 to 92 %
yield.
According to the process b) of the invention, if desired, the hydrochloride salt of the compound of formula (IV) can be fused with cysteamine hydrochloride in the presence of an inert organic diluent whi~h does not dissolve any of the starting hydrochlorides. The use of such diluents can be particularly advantageous when the process of the invention is used for a large-scale production. Aliphatic, aromatic or halogenated aliphatic hydrocarbons may suitably be employed as diluents. Preferably benzene, toluene, dichloroethane or petroleum ether (with a boiling point of 60 to 100C) - lL -nay be used as diluents for this fusion reaction.
From the dihydrochloride of the base of formula (II) obtained in this way, the monohydrochLoride o~ the base of formula (II) can be prepared ancl reaoted with L-methyLthio-L-me-thylamino-2-nitroethylene of the formuLa (III) in the manner mentioned above.
The reaction mi~ture, obtained as a result of the process of the invention, essentiaLLy contains the hydrochLoride of the base of for~uLa (I), t~hich crystaLLizes out from the mi~ture opti~naLLy after adding an appropriate solvent or soLvent mi~ture, e,g, aqueous ethanoL or a mi~ture of ethQnoL with acetone to the reaction mi~ture, The puri-ty of the h~drochLoride of the base of formula (I) obtained in the reaction of the in~-ention is at Least of 9~ ,~o. If desire~, this product may further be purified by using chromatography ancl~or fractional crystaLlization.
The hydrochLoricle of 5-dimethyLaminotnethyL-2--f~rfur~L aLcohoL of the formuLa (IV) used in process b) of the invcntion is a known substance ~J. .-~m. Chem, Soc, 69, 4S4 (L947)~, The cysteamine h~drochloride is commerciaLLy avaiLabLe, The advantages of the process of the invention can be summarized as foLLows, When the direct aim is to prepare -the hydro-chLoride of the base of for~ula (I), it is not inevitabLy needed to prepare and separate the base of formuLa (I) 7~
in a separate step for forming the hydrochLoride. ~his is particularly advantageous, as the preparation of the base of formuLa O in a pure, crystaLLine f~ m according to the prior art is probLematio.
By using -the process of the invention, the hydrochLoride of the base of formuLa (I) is directl~ ob-tainecl in an advantageous cr~-stalLine form~.
The voLume demand of the process of the inven-tion is ver~ Low~ as no separate addition of any soLvent to the react~nts is needed.
Basecd on these facts, the process of the inven-tion is useful for the simple preparation of the base of formula (I) arld its h~drochLoride in a good yieLc] at Qtl indùstriaL scale, too.
The nel~ dihydrochLoride saLt of the base of formuLa (~) prepared accorcling to the process of the invention is a weLL-defined, stabLe compound that can be stored ~rithout aLteration and from ~hich, if desired, the base of formula (II) or the ne~ monoh~drochLoricle saLt thereof can be prepared at any time, suitabLy shortLy before the use.
The process of the invention is iLLustrated in cletaiL by the foLLowing non-Limiting e~ampLes.
Example L
Preparation of 2 [(2-aminoethyL)-thiomethyL]--~-dimeth~Laminomethylfuran dihydrochLoride [dihydrochLoride of the ba~e of formuLa (~) -A mixture containing cysteamine hydrochloride (9.08 g, 0.08 mole) and 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (15.32 g, 0.08 mole) is fused while stirring at 70 to 75 C, then concentrated hydrochloric acicl ~0.75 ml) is added and the mixture is stirred further at 80 C for one hour and at 90 C for 20 minutes under mildly reduced pressure (40 to 60 KPa). After cooling to 70 C, abs.
ethanol (15 ml~ is added and the reaction mixture is kept at room temperature for 2 hours, then abs. acetone (15 ml) is added, the mixture is kept at 0 to 4 C overnight, the crystalline precipiatate is filtered, washed and a 1:1 mixture of ethanol and acetone and dried to give 20.19 g (87.2~) of the aimed product, m.p. 160 to 162 C.
Example 2 Preparation of 2-[(2-paminoethyl~-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride. A mixture containing cysteamine hydrochloride (14.7 g, 0.13 mole), 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (23.0 g, 0.12 mole) and concentrated hydrochloric acid (5 ml) is heated to 60 C under stirring within a few minutes. After about 10 minutes, a melt is formed which is let to cool to room temperature, stirred at room temperature for 6 hours and set aside at room temperature for 60 hours. The crystalline mixture is suspended in ethanol (100 ml), dissolved hy heating to the boiling point, cooled rapidly while stirring, kept 7~3'~
at 0 to 5 C for one hour, filtered, ~iashed with iee--coLd ethanoL anc~ dried to give 25 g (72.5 ~0) of the aimed produet, m.p, 163 to L65 C after ree~ystaLlization from 96 $ ethanol, E~ample 3 Preparation of 2-C(2-aminoethyL)-thiomethyLj--5-dimethylaminomethylfuran dihydrochLoride A mi~ture eontaining cysteamine hydrochLoride L0 (L9.0 g, o.L67 moLe) and ~-dimethyLaminomethyL-2-furfur~L
aLcohoL hydrochLoride (32.0 D~ o,L6'3 moLe) is fused at 67 C, then eoncentrated hydrochLoric acid (L.0 ml) is added. The temperature is increased t~ 90 C ~ithin 16 rninutes, a fur-ther amount of concentrated hydroehLoric L5 acid (0.5 mL) is added, the mi~ture is stirred at this temperature for 40 minutes, cooLed to 80 C and abs, ethanol (9~ ml) is added, The cr~-stalline mi~ture is thoroughly stirred, eooled, filtered, ~iashed ~ith abs, ethanoL and dried to gi~e 40r L g (83.7 ~o as ealeulated for e~-ste~mine hydroehloride) of the aimed procluet, m.p. L59 to L61 C.
E~ampLe 4 Preparation of 2-[(2-aminoethyL)-thiomethyl~-2~ -~-dimethylaminomethyLfuran dihydrochLoride A mixture eontaining eysteamine hydroehloride (29.4 g, 0.26 moLe) and 5-dimethyLaminomethyL-2-furfuryl aLeohoL hydroehLoride ~45.96 g, o,24 moLe) is meLted - L~ -while stirring in a water bath kep-t at 70 to 7~ C.
After reaching an internal temperat~e of 60 a (about 30 minutes), concentrated hydrochLoric acid (3.6 mL) i9 added dropwise within L0 minutes, -then t~e mi~-ture 5 is stirred at 60 C for 3 hours and at 70 C Por L ho~, Abs. ethanol (60 mL) is added, then the mi~ture is Let to cool ~o 40 oc~ ace-tone (60 ml) is adcled, s-tirred for 2 hours at room temperature and then kept at ~ to L0 C
overnigh-t. The crystaLs precipitated are colLeoted, L0 washed with ethanoL and acetona and clried in the air to gi~-e ~.4 g (80.4 ~) of the aimed product, m.p. L~8 to L60 C.
E~am~Le ~
L~ Prcparation of 2-[(2-aminoethyL)-thiomethyl]--~-dimethyLaminomethyLfuran dih~drochLoride A mi~ture containing cysteamine hydrochLoride (9.08 g, 0.08 moLe), ~-dimethyLaminomethyL-2-furfuryL
aLcohoL h~-drochLoride (L~.32 g, 0.08 moLe) arld water (L
mL) is heated to 30 C under stirring to give a homogeneous melt, then concentrated hydrochLoric acid (o.6 mL) and a soLution of ethyL chLorosuLphite (0.~ mL, prepared in the manner cl~scribed beLow) are ~dded ~ithin L0 minute9, whereupon the mi~ture is stirred at 60 C for 3 hours, 2~ and at 70 C for one hour. Abs. ethanoL (20 mL) is added, then the mi~ture is Let to cooL to 40 C~ aeetone (20 mL) is added, stirred at room -temperature for 2 hours and kept at ~ to L0 C overnight. Thereafter, the process described 3~3~
- L6 _ in ExampLe 4 is followed to give 19.48 ~ (84.8 ~) of the aimed product, m.p. 158 to 160 C.
~ he solution o~ ethyL chLorosuLphite is pre~
pared by dropping -thion~L chLoride (2.8 mL) -to abs.
ethanoL (10 ~1) kept at -20 C, then stirring the soL-ution at -L0 C for 30 minutes.
ExampLe 6 Preparation of 2-C(2-aminoethyl)-thiomethyL~--5-dimethyLaminomethylfuran dihydrochLoride A mixture containityg cysteamine hydrochloride (4.~4 g~ 0.04 moLe) and 5-dimethyl~ninolnethyl-2-furfuryL
alcohol hydrochLoride (7.66 g~ 0.04 mole) is fused at 70 to 7~ C ~hiLe stirring) concentrated hydrochLoric acid (O.L8 ml) is added~ heated to 80 C, p-toLuenesul-phonic acid (0.~ g) is added, then stir~ed at 80 C for one hour and at 90 C for 20 minutes under miLdLy re-duced pressure (40 to 60 KPa). Aft~r cooLing down, the reaction mixture is worked up as described in ExampLe L
to give 9.83 g (85.4 ~) of the aimed product, m.p. 1~8 to L60 C.
Exa~ple 7 Preparation of 2-[(2-aminoethyL)-thl~methyl~--5-dimethylaminomethylfuran dihydroch]oride The prooe3~ described in Example 6 i9. foLLowed, except that 8~ ~ phosphorio acid (0 3 ml) i9 used instead of p_toluenesuLphonic acid to give 9.8 g (8~.3 ~) of the .
-~3 1~7 aimed product, m.p. L58 to 160 C.
E~ample 8 PreParatiOn of 2-[(2-aminoethyL) thiom0thyL~--3-dimethyLaminomethyLfuran dihyclrochLoride A mixture containing cysteamine hydrochluride (9.08 ~, 0.08 moLe)and 3-dime~hylaminomethyL-2-furfuryl aLcohoL hydrochLoride (L3.32 g, 0.08 mole) is fused at 78 C, thionyL chLoride (0.2 m~) is added, and stirred ~o at 80 C for L0 minute~, then at 80 C for 30 minutes and at 90 C for 20 minutes under miLdLy reduced pressure, After cooLing to 70 C, abs. ethanoL (20 mL) is added, heated to boiLin~, a further amount of abs. ethanoL
(20 mL) and acetone (40 mL) are added, and kept at ~ C
L~ overni~ht. The crystaLLine precipitate is washed with a L:l mi~ture of ethanoL and acetone and dried to give L9,6 g (8~.3 ~0) of -the aimed product, m.p. L~6 -to L38 C.
E~ampLe g .
Preparation of 2-[(2-aminoethyL)~thiomethyL~--~-dimethylaminomethyLfuran dihydrochloride The process described in E~ample 8 is ~ollowed, except that aLuminium chLoride (L g) is used, instead of thionyL chLoride, to ~ive 2L.1 g (9L.9 ~) of the aimed 23 product.
E~ampLe L0 Preparation of 2-~(2-aminoethy-L~-thiomethyL]-:1~ 7~3~B
-~-di~ethylaminomethylfuran dihydrochloride An intimate mixture containing ~-dimethyLamino-methyL-2-furfuryl alcohol hydrochLoride (9~ 7~ g, 0.~
moLe), cysteamine hydrochLoride of 9Z % (64 g, 0.~2 moLe) and concentrated hydrochLoric acid (9.3 mL) i~ stirred in the presence of benæene (2~0 mL) at 60 to 62 C for 4 hours The benzene is decanted, the residue is stirred with abs. ethanoL (23~ ml) in a water bath of 80 C for some minutes, then acetone (23~ mL) i9 added, the mi~ture L0 is stirred and then kept at 0 to 4 C overnight. The crystaLLine precipitate is fiLtered, washed and dried to ~ive 124.5 ~ (86.7 ~) of the aimed product, m.p~
L6L to L64 C.
Whan 3.8 g of this prod~ct is recr~staLLi~ed L5 from ethanol (6 mL) and while cooLing acetone (6 mL) is added, 3.59 g of an anaLytical specimen are obtained, ~,p. L63 to 166 C.
ExampLe Ll Preparation of 2-~(2-aminoethyl)-thiornethyl~_ -S-dimethyLaminomethylfuran dihydrochLoride The proces~ described in ExampLe 10 is folLowed, except that, instead of benzene~ dichloroethane is used a~ diluent, with stirring at the boiling point for 3.~
2~ hours. The aimed product i9 obtained in a yield of 89 ~0, m.p L~7 to 16L C.
3X~
,9 E.Yample L2 Preparation of 2-[(2-aminoethyl)-thiomethyL~--~-dimethylaminomethylfuran dih~rclrochloride The process described in E~ampLe L0 is f'olLo~ed, 5 e~ccept that~ instead o~ benzone, petroleum ethor (with a boiLing point oP 70 to 80 C) Ls used as a cliLuent.
Tha aimed product i~ obtained in a 83 ~0 yield, m.p.
160 to L62 a.
E~cample L3 Preparation of 2-[(2-aminoethyL)-thiomethyL~--5~dimethylaminomethyLfuran base [base of the formuLa (II)~ from its dihydrochLoride To a mixture containing 2-C(2-aminoethyl)-15 -thiomethyl~ dimethy~aminomethylfuran dihydrochloride (38.6 g, 0.134 mole) and water (19 ml), sodium hydro}~ide solution of 40 aJ0 (29 ml) is added and the base is e~ctract~
ed into ethyL acetate (3 times 30 ml). rhe organic Layers are combined, dried o~er anhydrous potassiw~ carbonate, 20 filtered, the solvent is evaporated and the residue is distilLed under reduced pressure b~ using a Vigrewc dephLegmator. The aimed product is obtained in a ~ieLd of 22.8~ g (79.4 ~), b.p. L16 to 120 C/L3.3 Pa.
ExampLe 14 Preparation o~' 2-[(2-aminoethyL)-thiomethyL]--~-dimethylaminomethyLfuran monohydrDchLoride [monohydrochloride of the base o for~ula (II)]
3~
_ 20 -rO a suspension containin~ 2-C(2-aminoethyl)--thiomethyL~-5-dimethyLaminomethyLfuran dihydrochLoride ~2.87 g, O.OL moLe) in abs. ethanoL (25 mL)~ a soLution of potassium hydrogen carbona-te (1.0 g, O.OL mol0) -ln water (4 ml) is added under stirrLng a-t 20 C. The ml~-ture is stirred for 30 minutes, the precipitated potas3ium chLoride i9 fiL-tered and the solution evap?rated to dry-ness, The residue is triturated with ether, fiLtered, washed with ether and dried to give 2.42 g (96 ~) of the L0 aimed product, m.p, L15 to LL6 C.
E~ample L~
Preparation ~f 2-C(2-aminoethyL)-thiomethyL~--~-dimethyLaminomethyLfuran monohydrochloride A solu-tion of 2-~(2-c~ninoethyl)-thiomethyL~--5-dimethyLaminomethylfuran base ~2L.4 g, O.L moLe) in methanol (50 ml) is added dropwise to the soLution of 2-~(2-aminoethyl)-thiomethyL]-5-dimethyLaminomethyLfuran dihydrochLoride (28.7 ~, O.L moLe) in methanoL ~300 mL), then the mixture is stirred for ten minutes and then evaporated to dryness under reduced pressure, The residue i9 triturated with ether (100 mL)~ kept at 0 to 4 C for 2 hours, fiLtered, washed with ether and dried at 20 C
to give 48 g (89 %) of the aimed product, m.p. llL to 112 C.
Example 16 Preparation of 1-~2-[t-dimethylamminomethyl-2-(furylmethylthio)-ethyl))-amino-l-methylamino-2-nitroethylene hydrochloride [hydrochloride of the base of formula (I)]
A mixture containing 2-[(2-aminoethyl)-thiomekhyl]-5-dimethylaminomethylfuran monohydrochloride (12.54 g, 0.05 mole), l-methylthio-l-methylamino-2-nitroethylene (7.41 g, 0.05 mole) and water t2.5 ml) is fused at 70 to 75 C with stirring for 2 hours. Gas evolution is observed. After cooling, the reaction mixture is dissolved in ethanol (70 ml), clarified first by activated charcoal, then by Hyflo, the pH value of the filtered solution is adjusted to 5 by co~centrated aqueous hydrochloric acid, cooled to O C, inoculated and stirred at O C for some hours, then kept at O
to 4 C overnight. The precipitate is filtered, washed with abs. ethanol and dried at 50 C under reduced pressure to give 6.1 g (34.8 ~) of the aimed product, m.p. 139 to 141 C.
From the mother liquor, an additional amount of 3.8 g (21.7 ~) the aimed product of similar guality is obtained, m.p. 139 to 141 C.
Example 17 Preparation of 1-(2-[5-dimethylaminomethyl-2-(furylme-thylthio)-ethyl])-ammino-l-methylamino-2-nitroethylene hydrochloride A solution of postassium hydrogen carbonate _ ~2 -(1.0 g, 0.01 m3Le) in water (4 rnL) i9 added to 2-C(2--~minoethyl)-thionnethyL~-3-dimethyLaminomethyLfuran dihydrochLoride (2.87 g, 0.0] moLe). After stirrin~ for 10 minutes, l-me-thyLthio-L-methylamino-2 nitroethyLene (L.~2 g, O.OL02 moLe) is added~ the mi~ture is stirred at 40 to 30 C for L ho~r, heated to 60 C within lV
minutes, stirred at 60 C for L hour and at 70 C for 30 minutes. After cooling, abs. ethanol (30 mL) is added, the precipitated potassi~un chLoride is fiLtered out and the fiLtrate is e~aporated to dryness ~nder reduced press~e. rhe resid~le is clissoLved in 96 ,~o e-thanoL (L3.8 mL), the pH vaLue of the soLution is ~djusted to 5.5 to 6 by adding a fe~ drops of aqueous conc~nt~ated tlyCI~O-chLoric acid, stirred at 0 C for 3 hours nnd ~ept at 0 to 4 C overnight. The precipitate is fiLtered and treatecl as described in E~ampLe L6 to gi~e L.~7 g (~0.5 '~0) of the aimed product, m.p, L38 to L40 C.
From -the mother Liq~or an additionaL amount of O.L9 g (3.4 ~ of the aimed prod~lct is obtained, m.p. L38 to L40 C.
E~lpLe L8 Preparation of L-~2-~3-dimethyLaminollleth~L-2--(fur~LmethyLthio)-ethyL~?-amino-l-meth3rLatnino--2-nitroethyLene hydrochLoride A solution of potassi~n hydrogen carbonate (5.0 g, 0.03 moLe) in water (20 ml) is added to 2-~(2--aminoethyL)-thiomethyL]-3-dimethyLaminomethyL~ran .
~'~7~3~3~
- 2~ -dihydrochlor~de (L4~3S g, O.OS moLe). After stirring for L0 minutes, ].-methyLthio-L-methyLamino-2-nitro-ethylena (7~4~ g, 0.0~ ~ol0) is added, the mixture is ~tirred at 40 to S C for one hour, heated to 60 a within L0 minutes, stirrod at 60 C for one hour and at 70 C for 30 minute~. ~hereafter, the reaction mixture i9 diLuted with water (30 ml)~ the pH vaLue pf the soL-ution is adjusted to 5 by adding 2N aqueous hydrochLoric acid and extracted with chLorofor~ (2 times 30 mL). The pH ~aLue of the aqueous Layer is adjusted to L0 by usin~
2N aqueous potassium hydroxide soLution and extracted into chLorofor~ (four times 30 ml). The combined organic phase is dried over anhydrous sodiwm suLphate and evap-orated to dryness under reduced pressu~-e. ~he residue is dissoLved in abs. ethanoL (70 mL) and clarified by usin~
at first activated charcoal and then Hy-fLo. Aqueous concentrated hydrochLoric acid i9 added dropwise to the fiLtrate in order to adjust the pH ~aLue -to ~ S to 6, then the mixture is stirred (optionaLLy after inocuLation) at 0 C for 3 hours and kept at 0 to 4 C o~ernight. The precipitate is fiLtered and treated as described in Example 16 t~ gi~e 7.1 g (39 ~) of the aimed product, .p. 139 to 141 C.
From -the mother Liquor an additional amount of 3.~ g (L9 ~) of the aimed product i~ obtained, m.p~
L39 to L4L C.
93~
Example 19 Preparation of 1-(2-[5-dimethylaminomethyl-2-tfurylme-thylthio)-ethyl])-amino-1-methylamino-2-nitroethylene hydrochloride-2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran monohydrochloride prepared in situ in an amount of 0.01 mole as described in Example 17 is mixed with 1-methylthio-l-methylamino-2-nitroethylene (1.48 g, 0.01 mole) and stirred at room temperature for 8 hours, kept at room temperature for 14 hours and then stirred at the same temperature for one hour. Water (40 ml) is added, the pH
value of the solution is adjusted to 5 by adding 2N
hydrochloric acid, the mixture is extracted with chloroform (3 times 10 ml~, then the pH value of the a~ueous phase is adjusted to 10 by adding 2N aqueous potassium hydroxide solution and extracted into chloroform (4 times 20 ml~. The combined organic phase is dried and evaporated under reduced pressure. The remained crude base is dissolved in abs.
ethanol (4 volumes), clarified and filtered. The pH value of the ethanolic solution is adjusted to 5 by adding aqueous concentrated hydrochloric acid at 0 C. THe solution is inoculated, stirred at 0 C for 3 hours and kept at 0 to 4 C
overnight. The precipitate is filtered, washed with ethanol and dried to give 1.05 g ~29.9 %) of the aimed product, m.p.
13g to 141 C.
From the mother liquor, Q.9 g (26 %) of the aimed product is isolated, m.p. 138 to 140 C.
s~3~3~
- 2~ -F~onl the crude base of fonnula (I) obtained in the course of the working-up procedure, a crystaLline product can be obtained in a known manner, e.~. b~ re-crystaLLization froln 4-methyl-2-pentanone~ In~p- 67 ~o 6~ C.
Claims (24)
1. A process for the preparation of the hydro-chloride of 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methylamino-2-nitroethylene of formu1a (I) (I) which comprises reacting the monohydrochloride of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran of formula (II) (II) with 1-methylthio-1-methylamino-2-nitroethylene of formula (III) (III)
2. A process according to claim 1, in which the monohydrochloride of formula II 9s prepared by reacting the hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of formula (IV) (IV) with cysteamine hydrochloride at a temperature between 20 and 120 °C without the addition of solvent in the presence of a catalytic amount of a mineral acid, or a substance furnishing under the reaction conditions a mineral acid and, then liberating therefrom the monohydrochloride of the base of formula (II).
3. A process according to claim 2, in which the catalyst also contains an organic acid having a pKa value of 0 to 2.
4. A process according to claim 2, in which the reaction of the compound of formula IV is effected in the presence of an inert organic diluent.
5. A process according to claim 2, in which the dihydrochloride is separated and then converted to the mono-hydrochloride.
6. A process according to claim 2, in which the monohydrochloride is generated from the dihydrochloride in situ.
7. A process according to claim 2, 5 or 6, in which the dihydrochloride is converted directly in the monohydrochloride.
8. A process according to claim 2, 5 or 6, in which the dihydrochloride is converted into the free base which is then converted to the monohydrochlodide.
9. A process according to claim 1, in which the free base is liberated from the hydrochloride product.
10. A process according to claim 1, 2 or 3, in which the hydrochloride is separated from the reaction mixture and purified.
11. A process according to claim 9, in which the free base is purified and converted to the hydrochloride.
12. A process according to claim 3, which compri-ses using p-toluenesulphonic acid as an organic acid with a strength similar to that of a mineral acid.
13. A process according to claim 2, 3 or 4, which comprises using thionyl chloride as a compound furnishing a catalytic amount of a mineral acid.
14. A process according to claim 1, 2 or 3, which comprises reacting the monohydrochloride of the base of formula (II) with 1-methylthio-1-methylamino-2-nitroethylene of formula (III) at a temperature between 20 and 90°C.
15. A process according to claim 2, 3 or 4, in which the reaction of the compound of formula IV is effected at a temperature from 20 to 75°C.
16. A process for the preparation of the dihydro-chloride of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran of formula (II) (II) which comprises reacting the hydrochloride of 5-dimethyl-aminomethyl-2-furfuryl alcohol of formula (IV) (IV) with cysteamine hydrochloride at a temperature between 20 and 120°C without adding a solvent in the presence of a catalytic amount of a mineral acid, or a catalytic amount of a substance furnishing under the reaction conditions a mineral acid.
17. A process according to claim 16, in which the catalyst also contains an organic acid having a PKa value of 0 to 2.
18. A process according to claim 16, in which the reaction of the compound of formula IV is effected in the presence of an inert organic diluent.
19. A process according to claim 16, in which the dihydrochloride is separated and then converted to the monohydrochloride.
20. A process according to claim 16, in which the monohydrochloride is generated from the dihydrochloride in situ.
21. A process according to claim 16, in which the dihydrochloride is converted directly in the monohydrochloride.
22. A process according to claim 16, in which the dihydrochloride is converted into the free base which is then converted to the monohydrochloride.
23. 2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran dihydrochloride.
24. 2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran monohydrochloride.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU2515/83 | 1983-07-15 | ||
| HU2514/83 | 1983-07-15 | ||
| HU251583A HU193497B (en) | 1983-07-15 | 1983-07-15 | Process for preparing sanitidine hydrogen halogenides |
| HU251483A HU193496B (en) | 1983-07-15 | 1983-07-15 | Process for production of basic tioether and it salts i |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1279328C true CA1279328C (en) | 1991-01-22 |
Family
ID=26317525
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|---|---|---|---|
| CA000458870A Expired - Fee Related CA1279328C (en) | 1983-07-15 | 1984-07-13 | Process for preparing basic thioethers and the salts thereof |
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| Country | Link |
|---|---|
| KR (1) | KR910007966B1 (en) |
| AR (1) | AR242029A1 (en) |
| AT (1) | AT389873B (en) |
| CA (1) | CA1279328C (en) |
| CS (1) | CS248717B2 (en) |
| DK (1) | DK162525C (en) |
| ES (1) | ES534363A0 (en) |
| FI (1) | FI88157C (en) |
| MX (1) | MX159694A (en) |
| NO (1) | NO842904L (en) |
| SE (1) | SE457082B (en) |
| SU (1) | SU1384197A3 (en) |
| YU (1) | YU45634B (en) |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
| BE886997A (en) * | 1980-01-08 | 1981-07-08 | Glaxo Group Ltd | PROCESS FOR THE PREPARATION OF RANITIDINE AND INTERMEDIATE PRODUCTS THEREOF |
| NO811501L (en) * | 1980-05-13 | 1981-11-16 | Crc Ricerca Chim | PROCEDURE FOR THE PREPARATION OF ETHENDIAMINE DERIVATIVES, AND INTERMEDIATES FOR THESE |
| ES8200358A1 (en) * | 1980-09-30 | 1981-11-01 | Inke Sa | PROCEDURE FOR OBTAINING N-2-5- (DIMETHYLAMINE) METHYL-2-FURANIL METHYL THIO-N-METHYL-2-NITRO-1,1-ETHENODIAMINE. (Machine-translation by Google Translate, not legally binding) |
| IL63968A (en) * | 1980-10-01 | 1985-10-31 | Glaxo Group Ltd | Form 2 ranitidine hydrochloride,its preparation and pharmaceutical compositions containing it |
| ES8200101A1 (en) * | 1980-12-03 | 1981-10-16 | Inke Sa | Procedure for the obtaining of N- (2- (((5- ((dimethylamino) methyl) -2-furanil) methyl) tio) ethyl) -n'-methyl-2-nitro-1,1-etenodyamine (Machine-translation by Google Translate, not legally binding) |
| ES497737A0 (en) * | 1980-12-13 | 1981-11-16 | Parellada Llauger Miguel | PROCEDURE FOR OBTAINING N- (2 - ((5 - ((DIMETHYLAMI-NO) METHYL) FURFURIL) THIO) ETHYL) -N'- METHYL -2- NITRO-1,1- ETHENO- DIAMINE |
| PT74235B (en) * | 1980-12-30 | 1984-01-04 | Glaxo Group Ltd | Process for the preparation of a furan derivative |
| FI84060C (en) * | 1980-12-30 | 1991-10-10 | Glaxo Group Ltd | FORM OF FRAMSTAELLNING AV N- / 2 - // 5 - / (DIMETHYLAMINO) METHYL / -2-FURANYLMETHYL / THIO / EECL / -N'-METHYL-2-NITRO-1,1-ETENDIAMINE. |
| ATE11536T1 (en) * | 1981-02-20 | 1985-02-15 | Glaxo Group Limited | PROCESS FOR THE PREPARATION OF A FURAN DERIVATIVE. |
| ES8300325A1 (en) * | 1981-05-02 | 1982-11-01 | Especialidades Farmaco Terape | Procedure for the obtaining of a compound derived from the furfurilico alcohol. (Machine-translation by Google Translate, not legally binding) |
| AR229878A1 (en) * | 1981-05-07 | 1983-12-30 | Glaxo Group Ltd | PROCEDURE FOR PREPARING RANITIDINE |
| 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) |
| ES507360A0 (en) * | 1981-11-20 | 1982-11-16 | Especialidades Latinas Medic U | PROCEDURE FOR OBTAINING N- (2-5-DIMETHYLAMINE, METHYL-2-FURANIL-METHYL-THIO-ETHYL-N'-METHYL-S-NITRO-ETHANE-DIAMINE. |
| ES8300327A1 (en) * | 1982-01-13 | 1982-11-01 | Barisintex Sa | Procedure for the obtaining of derivatives of aminoalkilfuranos. (Machine-translation by Google Translate, not legally binding) |
| ES8303391A1 (en) * | 1982-04-30 | 1983-02-01 | Inke Sa | Procedure for the obtaining of N-2- (5- (dimethylaminum) methyl-2-furanil) methyl) tio) ethyl) -n'-methyl-2-nitro-1,1-etenodyamine. (Machine-translation by Google Translate, not legally binding) |
| ES8302686A1 (en) * | 1982-05-19 | 1983-02-01 | Tabah Papo Marcelo | Procedure for the obtaining of a new furanical derivative of therapeutic interest. (Machine-translation by Google Translate, not legally binding) |
-
1984
- 1984-07-13 CA CA000458870A patent/CA1279328C/en not_active Expired - Fee Related
- 1984-07-13 AT AT0227284A patent/AT389873B/en active
- 1984-07-13 SE SE8403717A patent/SE457082B/en not_active IP Right Cessation
- 1984-07-13 YU YU122484A patent/YU45634B/en unknown
- 1984-07-13 SU SU843798790A patent/SU1384197A3/en active
- 1984-07-13 DK DK345284A patent/DK162525C/en not_active IP Right Cessation
- 1984-07-13 AR AR84297205A patent/AR242029A1/en active
- 1984-07-13 FI FI842822A patent/FI88157C/en not_active IP Right Cessation
- 1984-07-14 KR KR1019840004164A patent/KR910007966B1/en not_active IP Right Cessation
- 1984-07-16 CS CS845492A patent/CS248717B2/en unknown
- 1984-07-16 ES ES534363A patent/ES534363A0/en active Granted
- 1984-07-16 NO NO842904A patent/NO842904L/en unknown
- 1984-07-16 MX MX202037A patent/MX159694A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI842822A (en) | 1985-01-16 |
| SE457082B (en) | 1988-11-28 |
| NO842904L (en) | 1985-01-16 |
| YU122484A (en) | 1986-10-31 |
| FI88157C (en) | 1993-04-13 |
| KR910007966B1 (en) | 1991-10-04 |
| ATA227284A (en) | 1989-07-15 |
| ES8602732A1 (en) | 1985-12-01 |
| AT389873B (en) | 1990-02-12 |
| MX159694A (en) | 1989-08-07 |
| SU1384197A3 (en) | 1988-03-23 |
| YU45634B (en) | 1992-07-20 |
| DK162525C (en) | 1992-03-30 |
| KR850001187A (en) | 1985-03-16 |
| DK345284D0 (en) | 1984-07-13 |
| ES534363A0 (en) | 1985-12-01 |
| AR242029A1 (en) | 1993-02-26 |
| DK162525B (en) | 1991-11-11 |
| SE8403717D0 (en) | 1984-07-13 |
| SE8403717L (en) | 1985-01-16 |
| CS248717B2 (en) | 1987-02-12 |
| DK345284A (en) | 1985-01-16 |
| FI842822A0 (en) | 1984-07-13 |
| FI88157B (en) | 1992-12-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |