METHODE DE PREPARATION DE 2-[[[5-(DIMETHYL- AMINO)METHYL-2-FURANYL] METHYL] THIO] ETHYLENEAMINE

PROCESS FOR THE PREPARATION OF 2-[[[5- (DIMETHYLAMINO)METHYL-2-FURANYLMETHYLTHIO FURANYL]METHYL]THIO]ETHANEAMINE ETHANEAMINE

Abrégé anglais

ABSTRACT
A new process for the preparation of 2-[[[5-(dimethyl-
aminol-methyl-2-furany] methy] thio]ethaneamine of the formula
<IMG>
is described, wherein 2-[[[5-(dimethylamino)methyl-2-furany] -
methyl] thio]ethanol of the formula
<IMG>
is halogenated to the corresponding halogenide of the formula
<IMG>
wherein Hal is chlorine or bromine, and the resulting compound is
aminated with ammonia to yield the desired compound.
The desired compound represents a valuable intermediate
for the preparation of the therapeutically important compound
ranitidine, which is used for the treatment of ulcer diseases.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 2-[[[5-(dimethylamino)-
methyl-2-furanyl] methy] thio] ethaneamine of the formula
<IMG>
characterized in that in 2-[[[5-(dimethylamino)methyl-2-furanyl]
methyl] thio]ethanol of the formula
<IMG>
the primary alcoholic hydroxy group is halogenated to give the
halogenide of the formula
<IMG>
wherein Hal is chlorine or bromine, and the resulting compound is
aminated with ammonia to yield the desired compound.
2. A process according to claim 1, characterized in that
the primary alcoholic hydroxy group is halogenated with SOCl2 in
methylene chloride at room temperature or with a solution of HBr
in acetic acid.
3, A process according to claim 1, characterized in that
the amination with ammonia is carried out at reflux temperature of
the reaction mixture.

Description

774gl
A P~OCESS FO~ T~E ~EP~ATION OF 2-[[[5~(DIMETHyLAMINo)METH~L
2-FURA~YL] METHYL~ THIO] ETHANEAMINE
The present invention relates to a new process for the
preparation of 2-[[[5~(dimethylamino)methyl-2 furany~ methyl]thio]
ethaneamine of the formula
o
3~NCH2 i ~2scH2cH2NH2
This compound is a valuable intermediate in the synthesis of N-[2-
[[[5-(dimethylamino)methyl~2~furanyl]methyl~thio]ethyl]-N~-meth
2-nitro-1,1-ethenediamine, a compound known under the genaric name
ranitidine, Ranit~dine was first described in the German Publication
27 34 070 as a selective H2-antagonist, i.e. a compound which in-
hibits the secretion of gastric acid, which is stimulated by the
histamine-H2~receptoxs. Ranitidine represents preferably in the
form of its hydrochloride, a valuable medicine for the treatment of
ulcer diseases,
The above-stated German Publication also describes a method
for the synthesis of the intermediate 2-[[[5-(dimethylamino)-methyl-
2-furany~ methyl] thio~ ethaneamine, wherein the starting compound
5-(N,N-dimethylamino)-methyl-2-hydroxymethylfuran of the formula
(CH3)2NCH2 / ~ / CH2
is reacted with cisteamine-hydrochloride (Example A of the mentioned
German Publication), the yield being 54%. The starting compound
5-(N,N~dimethylamino)methyl-2-hydroxy-
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methylfuran is a known compound, which can be o'btained ingood yield (70 %) from 2-furan-methanol (furfuryl alcohol)
by means of Mannich's reaction in the manner described by
Gill and Ing, J.Chem.Soc. 4728-4731 (1958).
A disadvantage oP this method resides in the use of c-ysteamine
hydrochloride, which is an extremely expensive chemical.
~urthermore, the yields of the reaction are poor. ~dditionally,
the reaction takes up quire a long period of time.
~he object of the present invention is to provide a process
for the preparation of 2-[[[5-(dimethylamino)methyl-2-furanyl]-
methyl]thio~ethaneamine with good yield, avoiding the use of
the extremely expensive and not readily available cysteamine
hydrochloride and thereby substantially affec-ting the economy
of the reaction.
4ccording to the invention this object is achieved by reacting
2-[[[5-(dimethylamino)me-thyl-2-furanyl~methyl~thio~ethanol of
the formula
(CH3)21~C~2 ~ CH2SCH2CHzO~I
with SOCl2 in methylene chloride or with a solution of HBr
in acetic acid to give the corresponding halogenide of the
formula
(Ci3)2NGl2 CH2SCll2C~2-~lal
wherein ~al is preferably chlorine or bromine, whereupon the
thus obtained compound is amina-ted with ammonia to yield 2-[[[5-
(dimethylamino)methyl-2-furanyl]methyl~-thio]ethaneamine of
- - ~ - ~ . .
,
.

- ~- 1177~gl
the formula
(CH3)2NCH2 ~ ~ CI~2scH2c~I2NH2
The starting co~pound 2-[[[5-(dimethylamino)methyl-2-furanyl~-
methyl]thio~ethanol can be obtained in accordance with the
known methods from 5-(N,N-dimethylamino)met'nyl-2-hydroxymethyl
furane or from 2-[[[2-furanylimethyl]thi.o~ethanol.
The invention is illustrated by the following non-limitative
Examples.
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7 ~ ~ g l
Example 1
2-[[[5-(dimeth~lamino)meth~Jl-2-furan~l~m_t~I~lJthio~ethanechloride
h~drochloride
2-[[~5-(dimethylamino)methyl-2--fur~nyl~methglJthio]ethanol
(0.5 g, 2.3 mmole) is dissolved in methylene chloride (7 ml).
A solution of SOC12 (0.5 ml) in methylene chloride (3 ml)
-is added dropwise under stirring at room temperature. After
30 minutes the reac-tion mixture is evaporated. There are obtained
0.42 g of the crude product.
~xample 2
2-[[[5-(dimeth~lamino)meth~l-2 fur~yl~meth~l]thio]ethaneamine
Crude 2-[[[5-(dimethylamino)methyl-2-furanyl~methyl]thio~ethane-
chloride hydrochloride (0.42 g) obtained in Example 1 is
dissolved in methanol (30 ml). The solution is refluxed while
passing through it gaseous ammonia Eor 4 to 5 hours. The
solvent is then evaporated, the oily residue is dissolved in the
least possible ~uantity of wa-ter, the resulting solution is
n~utralized with Na2C03 and extracted with ether. The etherial
extracts are dried with Na2S04, filtered and evaporated. Thus
there are obtained 214 mg of the desired compolmd (46 % with
respect to 2-[[[5-(dimethylamino)methyl-2-furanyl~methyl]-
thio~ethanol). Bop~ 104-106C (0.133 mbar).
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1 1~7~91
Example ~
2-[[C~N,N-dimeth~lamino)meth~l-2-furan~l~meth~l~thio]ethane~
chloride
2-[[[5-~N t N dimethylamino)methyl-2-furanyl~methylJthio]ethanol
(2.15 g, 10 mmole) is dissolved in methylene chloride (18 ml).
A solution of thionyl chloride (2.18 ml, 30 mmole) in methylene
chloride (9 ml) is added -thereto dropwise under stirring at room
temperature. ~he solution is stirred for another hour at room
temperature. The solvent is evaporated and methanol (25 ml),
saturated with ammonia, is poured on the red oily residue. Active
charcoal (100 mg) is added thereto and the resulting mixture
is filtered after 1 hour. The solvent is evaporated, ethyl
acetate is poured on the residual crude product, it is filtered
and ethyl acetate is evaporated. There are obtained 1.84 g (79 %)
of the desired product.
Rf = 0.58 (CHCl3 : MeOH = 5 : 1)
MS: m/e = 233 (M+)
H NMR (CDC13):9~ = 7-75 (s, -N(CH3)2); 7.05 - 7035 and 6-45 -
6.7 (two t, -CH2-CH2); 5.6 and 6.25 (two s, -CH2-);
3.9 (s, H3 4)
JCH2CH2- 7.5 H
Example 4
2-C[[5-(N~N-dimethyl-amino~methyl-2-furanylJmethyl]thio]ethane
chloride oxalate
Oxalic acid dihydrate (540 mg) is dissolved in ethyl acetate
(30 ml). A solution of 2-~[[5-(N,N-dimethylamino)methyl-2-
furanyl~methyl]thio]ethanechloride (l g) in ethyl acetate
is added dropwise thereto. l'he product which separated is
sucked off. There are obtained 0.94 g of the corresponding
oxalate, m.p. 87-91C.
H NMR (DMSO -d6):~ = 7.35 (s, -~(CH3)2); 7.2 and 6.3 (-two t,
-CH2-CH2-); 6.15 and 5.85 (two s, -CH2); 3.7
and 3.5 (d, H3 L~); 1.0 (broad, OH)
.
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3,4 JCM = 7-5 Hz
~nalysis for C12H18ClNOS
CalC.: 44.51 % C 5.60 ~/o H 4.33 'yo N
Found: 45.41 % C 5.30 ~/o H 4.76 '~o N
~xample 5
2-~[[~-(N,N-dimeth,ylamino~meth;yl-?--furan;yl~meth~l~-thio~ethane
amine
Aqueous a~onia solution (50 ml) is poured on 2-[[[5-(N,N-
dimethylamino)methyl-2-furanyl~methyl]thio]ethanechloride
(640 mg, 2.7 mmole? and it is stirred for 12 hours at room
temperature. ~he resulting aqueous solu-tion is extracted with
ethyl acetate (4 x 30 ml). The combined extracts are dried o-ver
Na2S04 and the solvent is evaporated. ~here are obtained 440 g
(75 %) of the desired compound. The NMR~ IR and MS of this
compound correspond to those of the authentic compound.
Exa~ple 6
.,
2-[[[5-(N,N-dimeth~lamino)meth~l-2 furan;Yl]meth~l]thio~ethane-
amine dioxalate
Oxalic acid (518 mg) is dissolved in ethyl ace-tate (26 ml).
A solution of 2-[[[5-(N,N-dimethylamino)methyl-2-furanyl]methyl~-
thio]ethaneamine (440 mg, 2.1 mmole) in ethyl acetate is added
dropwise thereto. ~he product which separates is sucked off.
There are obtained 690 mg (85 %) of the corresponding dioxalate,
m.p. 160-163C. ;
Analysis for C14H22N209S:
Calc.: 42.53 % C 5.61 % H 7.08 % N
Found: 42.55 % C 5.76 C/o H 7.24 % N
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