Note: Descriptions are shown in the official language in which they were submitted.
~L26~
PROC~SS FOR Pn~P~R~NG ~ BASIC THIO~rHER ~ND THL s~L~r
TH~R~OF
Thls inver~tion rela-tes to a new process for
preparing l- {2-[~-dimethylaminornethyl-2-(furylmethyl-
thio)-ethyl]~_am-Lno-l-methylamino-2-nitroethylene o~
tho forrmlla ~I)
H3 C
N-H~Cr,,~-CI12-S-(CH~)-NH-C-NII-CH3
~3C (I) C ~ - N 2
arld the hydrochloride thereo~,
Being a selective histamine ~-2 receptor anta-
gonist~ the compound of formula (I) (generic name:
ranitidine) is an outstanding cdrug against gastric and
cduodenal ulcers, For therapeutical purposes the hydro-
chloride of the cornpound of formula (I) is usecd,
Fo:r preparing the hyd:roch.loride of the com-
pound of` ~ormuLa (I), the following processes are, des-
cribed in the literature,
a) According to ~xample 32 (page 7~) reported in the
published German patent applica-tion No, 2,734,070,
2~ the hydrochloride of the compound of formula (I)
is prepared by dissolving the base of ~ormula (I)
in ethanol ancl precipitati~g the hydrochloride ~ormed
by adding ethyl aceta-te to give a 89,6 ~0 yield o~
the hydrochloride as calculated ~or the base
A 3632-67-PT
~LZ~:;Z9:~L3
-usc(l as starl;:Lrlg Inaterial
b) Accordin~ to ~alrlple l (pag~ 8) o~ -thc Belgian
pa-tent specification No, 890,~74, the hydrochlorlde
o~ -the compound of ~oxmula (I) is prepared by adding
concentrated aqueous hydrochloric acid to a solution
and precipitating the hydrochloride formed by aclding
a further amount of isopropa~ol to gi~e a 93,9
yield of the hydrochloride as calculated for -the
base,
Thus, the starting material for both processes
is the base of formula ~I), Therefore, based on the
processes known at prese~t, the base of -for~ula (I)
should first be prepared i~ an appropriate quality for
the formation of the hydrochloride, According to ~xample
l~ 24 (page 68) of the above-cited published German patent
applicatio~ No, 2,734,0707 this base is prepared by re-
acti~g first 2~~(2-aminoethyl)-thiomethyl]-~-dimethyl-
aminome-thylfuran of the ~formula (II)
N H2~ o, C H2 S (C H2) N H~
H3C
with l,l-bis(methylthio~-2-nitroethylene of the for-
2~ mula (III)
~Z~ lL3
~ - 3 -
S-CH3
., /
02N C H ~ C ( III)
~CH~
in acetonitrile solution at the refl~x t~mperature for
14 hours, then removing the solvent and boiling -the
: crude distillation residue und0r re~lux with a me-thano-
lic solutio~ (Hereinafter, this process is called as
literature process "A") According to the descrlption~
the yield is 79 9 5~ A considerable deficiency of -this
description consists in the Pact that the product of
the fir~t step of this two-step reac-tion is not charac-
l~ terized An other defici.ency is tha-t~ concerning the
~: final produot, ~xample 1~ (page 61) of the published
~:` patent application cited abo~e -Ls quo-ted where, howe~er,
>
the exact condltions for the recrys-tallization are not
gi~en, altllo1lgh thcy bear a decisi~e impor-tance both
on the yield and quality of the base of formula (I)
: While in~es-tigating the process described in
~xample 24 of this published German application, it was
found that by ~ollowing this process a ~ery irnpure oily
product was formed in the ~irst step which could be
2~ characterized by the formula (IV)
~,
_ L~ _
H3C
N-H~C~ob~- ( H2-s-(cH2)~ NH-C-S-CH3
H3C (I~) C H ~ ~ 2
from which, however, in the way described i.n the Fxample,
the base o~ -formula (I) could not be obtalned in a quality
suitable to prepare the hydrochloride of the base of for-
mula (I).
[~ccording to our experimen-ts~ the crude prod~
uct of formula (IV) prepared by using the method described
in the abo~e ~xample could only be purified and made homo-
geneous with high losses, in a tedious and complicated
1~ way (e g by column chromatography separa-tion)]. Further
on, it has been found that, by using the process described
in Fxa~ple 24, a base of the ~ormula (I) with a quality
satisfying the above requirements could not be prepared
e~en from a p~e compound of l-he ~ormula (IV)
For the prepara-tion of the base of formula (I)
an other process is repor-ted in the Hungarian patent
application No 1827/83 published under No. T/3111~,
according to which the compound o~ formula (IX)
S~CH3
O~N C H=C (IX)
N H~CH3
. .
~z~
i9 -tr~nsf`ormed to 1-methyl-3-nit:roketen~imine of the
form~ll.a (~)
02N CH--C-N-CH3 (v)
by using a heavy metal salt, e g silve:r nitrate or
cuprous chloride, in the presence o~ a proton-binding
agent, and the ~eteneimine of formula (V) is brough-t
into an addition reaction with the base of formula
(II) to gi~e the base of formula (I). This pate~t appli-
cation contai~s two ~xamples, none of which can, how-
e~er, be e~aluated as -the yields are not mentioned
~rhe purification process of the crude base of formula
(I) is also not reported~] Hereinafter, this process is
lS called as literature process "B" Co~cerning -the iden-
tity and quality of the product ob-tained, spectro-
scopical proofs are quoted which are, howe~er, not
described On the other hand~ ths product obtained is
statecl to be identical wlth the ranitidine base pre-
pared as described in ~xample 1~ of -the published Ger-
man patent application No. 2,734,070 Howe~er, accord-
ing to our own in~estigations this latter base is not
suitable to prepare ranitidi~e hydrochloride wi-th
satisfying purity.
2~ Thus, the aim of the present in~e~tion is to
provide a process for the preparation of the base of
~ormula (I) and of its hydrochloride, which renders
possible to produce thcse compounds in a good yield and
( , .
~Z~9
6 -
,~ in a si.mple way at an industrial sc~le, too,
Now i-t has been found -that thLs aim can e~-
tirely be achieved when a 1-~2-[~-dimethylaminome-thyl-
-2-(furylmethylthio)-e-th-y~ -amino-l-(subs-titu-ted thio)-
-2-nitroe-thylene o~ the ger..leral formula. (VI),
HC
N- H2C rOo,L C H2-S-(CH7)2 NH ~C-S-R
. H3C - C H-N~2
7 (~I)
wherein
R stands for an optional substi-tuted alkyl or
1~ oxoalkyl group as well as a~ aryl, aralkyl or
oxoaralkyl groupy
i~ in situ -transformed to 1-~2-[~-dime-thylaminome-thyl-2-
:1 _
~ urylmethylthio)-ethyl~-3-nitroketeneimine of the
I formula (VII)
~ r
N-~lzC~/L'CH2S-(CH2)2N=C-CH-NO~
H3C
2~ (VII)
in a simple wa.y and in an excellent yield and then
the keteneimine o~ the ~ormula (VII) is reacted with
methyl min~,
9~3
-- 7 --
Th:is recognition i5 surp:risi~ for a number
of reasons, Hither-to, ln -the litera-ture9 the simply struc-
tured ni-t.roketeneimine of the formula (V) cited in con-
nection with literature proce.ss "B" has only been known
which has been publishecl only recently. It was not
foreseeable tha-t the rather complicatedly structured
nitroketeneimine o~ the ~ormula (VII) can be formed
from a compound of the general formula (VI) wi-thin an
extraordinarily short time (i,e, within a few minutes)
without any alteration of -the molecular moieties not
participating in the aimed reaction of eith~r the start-
ing compound of the general ~ormula (VI) or the formed
product of formula (VII); similarly it could no-t be
expected that the complicatedlY structured nitrokètene-
: 15 imine of the formula (VII) goes into an addition reac-
tion with methylamine within a very short time to gi~e
a base of the formula (I) with a ~ery high purity and~
acoordin~ to our obser~ations, nearly without any side
:reaction,
Thus, the present in~ention rela-tes to a new
process for preparing 1-r2-[~-dimethylaminome-thyl-2-.
-/furylmethylthio)-ethy~ ~-amino-l-methylamino~2-nitro-
ethylene and its hydrochloride, which comprises react-
ing a 1-~2-[~-dimethylaminomethyl-2-(furylmethylthio)-
2~ -ethy~} -amino-l-(substituted -thio)-2-nitroethylene of
the general formula (VI), wherein
: R stands for an optionally substituted alkyl
~, '
~29~
-- 8
group containing 1 to 4 carbon a-toms or an
oxoallcyl, aryl, aralkyl or o~oaralkyl group,
wi-th an agen-t capable of splitting out a mercaptan, ln
an organic solvent, optionalLy in the presence of an
acid-binding agent, then reacting the in s:i-tu prepared
1-{[2-[~-dimethylaminomethyl-2-(furylrnethylthio)-e-thyll~-
-3-nitroketeneimine of the f`ormula (VII) wi-th methylamine
and ~inally, if desired, separating the obtained base of
fo:~mula (I), purifying it and/or, if desirecl, -transform-
ing it to its hydrochloride.
The compound of the formula (VII) formed asan intermediate in the process of the inventiorl is new
The formation of this compound has been supported by
the fact that on the interaction of 1-~2-[~-dimethylamino-
1~ methyl-2-(furylmethylthio)-ethy~ -amino-l-methylthio-
-2-nitroethylene [compound o~ the forula (IV)J with
silver nitrate sil~er me-thylmercaptide was obta-Lned
in a nearly quantitati~e yield, as -Lt is desoribed
below
One of the compounds of general formula (VI)
used for preparing the compound of formula (VII), name-
ly the compound of ~ormula (IV), can be considered to
be a known substance on the basis of comparison of the
gene:ral formula reported in the process ~ariant b) of
2~ claim 37 (page 7) of the published German paten-t appli-
cation No. 2,7347070 with ~amole 24 (page 68), al-though
no characteristics (including the chemical-name) of this
substance aro given No other compound of the formula
:.
~Z~9~3
- 9
(VI) is mon-t:Loned -in -this pa-tent appllcation, Accordirlg
~ to ~ample 1 of -the published European pate~t applica-
; tion No, 0,002,930, the compound of formula (IV) mel-ts
at 71 C, To the best of our knowloclge~ no othe.r com-
pound of the ~ormula (VI) has been described in the
literat~re, Thus, the co~pounds of general ~ormula (VI)
are new, e~cept the compound of formula (IV), These
- compounds may be prepared in a known manner by react-
j ing the base of formula (II) with a compound of the
f~rmula (VIII)~
S-R
2 N C ~ = C \ (VIII)
~ 15 S-R
wherein R is as defined abov0,
A part of the compounds of general form~tla
(VIII) ~s known [Ao-ta Chem, Scand, 21~, 2797 (1967);
Chem, Ber, 100, ~91 (1967)], The new compounds of the
general ~ormula (VIII) can be prepared in a known way.
As a compound of the general formula (VI),
the compound of formula (IV) is useful e,g, for pre-
paring the nitroketeneimine of formula (VII), Metal
2~ salts, motal oxides or finely distributed metals may
~ ba employed as agents capable of splitting off a mer-
'~ captan, It is convenient to use e,g, silver nitrate
~ or cuprous chloride as metal salts, Organic bases are
.
~26~3
_ 10 --
suitable acid-binding agents Bo-th the formation and
the reaction with me-thylalnine of the compund of ~or-
mula (VII) are preferably carried ou-t at a temperature
eq-ual -to or somewha-t lower than room temperature Or-
ganic solvents such as lower alipha-tic alcohols, e g
ethanol, may s-uitably be used.
~ Rreferre~ embodiment of the invention comprises
treating a solution or suspension of the compound of
formula (IV) in absolute ethanol with silver nitrate
at ~ to 30 C and adding methylamine after the precipita-
tion of the directly formed silver mercaptide, then filtar-
ing the reaction mixture, removing the solvent from the
filtrate and working up the residue in the -usual way,
wherein the residue consists of the base of formula (I)
1~ in addition to the appropria-te salt of methylamine If
desired, the thus-ob-tained rani-tidine is reorystallized
and, if desired, it is transformefl to its hydrochloride
An o-ther preferred ernbodirnent of the invention
oomprises adding dropwise an e-thanolic methylamine sol-
ution con-taining silver nitrate to the ethanolic suspen-
sion of the compound of ~ormula (IV)and then following
the process described above.
The advantages of the process of the invention
can be swnrnarized as follows
2~ _ Both steps of the process of the invention,
i e the formation and reaction with methylamine
of the cornpound of ~ormula (VII) rapidly pro-
ceed at a temperature equal to or somewhat
2~3
11
:Lower than room temperature, Thi.s fact results
in the stability of -the compound of formula
; (VII) which will not decompose and thus the
base of forl~ula (I) formed will not be con-ta~
~ minated by decomposition products, An other
result is the energy sa~ing, As a consequence
of -the short processing ti.me (production
period), the pool of the equipments can
e~ficiently be utilized.
- The rapid proceeding of the reaction is rendered
possible for -the most part by the fact that
methylamine, being i~ a gaseous form under
normal conditions, can be used in an optional
excess and after the reaction -this excess can
1~ easily be removed without any heat demand, In
a sharp contrast there-to~ when -the base of
~; formula (I) is prepared by using the abo~e-
-oited literature "B" process~ i,e, by -trans-
forming the compound of formula tIX) to the nitro
20 keteneimine of formula (V) and by bringing the
latter compound to an addition reaction with
the base of formula (II)~ then the bass of
formula (II) can only be usod in a stoichiometric
amount and thus the addition reac-tion cannot
2~ be accelerated by u~ing an excess o~ the base
of formula (II), since this base is unstable~
sensitive to heat, it can only bc removed
under a high vacuum at a higher temperature,
Ei2~L3
- 12 -
and a par-tial clecomposition of the base cannot
be avoided during clistillation, Thus, the ob-
tained base of form~la (I) becomes severely
contaminatecl by either the remained amount o~
the base or by -the decomposition products
arising from the distillation of -the excess
base of formula (II)~
- In contrast to the literature process "A",
wherein one mole of methyl mercaptan each is
liberated in both steps, this toxic gas is
bound in the form of a harmless, un~olatile
metal mercaptide in the process of the in~ention
and thus the en~ironmen-t is not polluted,
- The yield of the crude base of formula (I)
1~ obtained by using the process of the inven-
tion is nearly quantitati~e, This crude product
contains only a ~ery little amount of contamina-
tions (except the salt of the used acicl-binding
agent), By using a simple puri~ying process,
a completely homogeneous base of the
formula (I)~ which is useful in forming the
hydrochloride, is obtained in a very good yield
(about 7~ %), The thue-obtained hydrochloride
does not need any further purifi~ation,
2~ Base~ on these facts, the process o~ the in~en-
tion is useful for the gimple preparation o-~ the base of
formuia (I) and its hydrochloride in a good yield at an
industrial scale, too,
.,
, .
i2~3
3 --
The proce~ of the inverl-tion i9 illustra-ted
in detail by the following non-limiting ~xamples,
~xatnple 1
Preparation of 1-~2-[~-dimethylaminomethyl-2-
-(~urylmethylthio)-ethy~-amino-l-methylamino-
~2-nitroethylene Cbase of the formula (I)~
~1,0 g (0,30 mole) of ailver nitrate dissolved
in 4000 ml of absolu-te ethanol are added -to a solution
containing 99.S g (0,30 mole) o~ 2-[~-dimethylamino-
methyl-2-(furylmethylthio)-ethy~} -anlino-l-methylthio-
-2-nitroethylene [compound of the formule (IV)~ in 2500
ml of absolute ethanol a-t 10 C within one minute to form
immediately silver methylmercaptide, Then ~7 ml of a
1~ 29,2 ~ ethanolic methylamine solution are added and the
mixture is stirred a-t room temperature for 2 hours, The
precipitate (which is silver methyl mercaptide in a yield
o~' 98,1 ~p according to its weight and composition) is
filtered and the filtrate is evaporated -to dryness at
room temperature. The evaporation residue is taken up
in 600 ml of water and extracted eight times with 1200 ml
of ethyl acetate each while adjusting the pH value to 10,
if needed. The organic phase~ are combined, dried and
evaporated under reduced pressure, The crude ranitidine
2~ is obtained as an evaporation residue in a yield of 79 g
(81~ %),
For the preparation of the hydrochloride, the
~2,62913
- 14 _
crude rani-tldine base is dis~olve,d in 380 ml of absolute
' ethanol ~nd the pH va.Lue of the solution is adju~ted -to
' 5,5 by adding concentrated aqueous hydrochlorlc acid at
. 0 to 5 C, The mix-tuxe is s-tirred at 0 C for additional
;~ 5 40 minut~s,
-~ The crystalline precipitate is filtered out~
; washed w:ith ethanol and dried to give ranitidine hydro-
chloride in a yield of 57.45 g (54,6 ~0)~ m,p,: 143 C,
A second crop of 23,15 g (22,0 %) is obtained ~rom tha
mother liquor~ m,p, 143 C,
~ l-t2-[5-Dimethylaminomethyl-2-(furylmethyl-thio)-
,} -ethy~ -amino-l-methylthio)-2-nitroethylene [compound
of the formula (IV)] used as star-ting material can be
~' prepared e,g, according -to ~xample 1 of tho published
' 15 ~uropean patent application No, 0,002,930,
,
; ~xample 2
~ Preparation of 1-~2-[5-dime-thylaminomethyl-2-
-(furylmethylth~o~-ethy~ -amino-l-methylamino-
' 20 -2-nitroethylene [base of the formula (I)] and
; its hydrochloride
A solution containing 2,55 g (0,015 mole) of
sil~er nitrate in 200 ml of absolute ethanol is added
to a solution containing 5 g (0,01~ mole) of 1-~2-E5-
-dimethylaminomethyl-2-(furylmethylthio)-ethy~ -amino-
-l-methylthio-2-nitroethylene [compound of the formula
(IV)] in 125 ml of absolute e-thanol within one minute
while stirring at 6 C to form immediately silver methyl-
~6f~ 3
mercapticl~ The mix-ture is st:Lrred at ~ C ~or additional
3 minut~s, -then 30 ml of a 27 ~ e-thanollc m~-thylamine
solution are addecl. The mix-ture is stlrred a-t room tempera-
-ture ~OI` 2 hours and then filtered. The filtrate is set
aside at ~ C overnight~ filtered again and -the ~i]-trate
is evapora-ted at room temperature under reduced pressure
After adding ~0 ml of water to the residue, -the pH val-ue
is adjusted to ~ 5 by adding 1 N aqueous hydrochloric
acid The mixture is extracted twice wi-th 70 ml of dichloro-
methane each, then the pH value of the a~ueous phase isadjusted to lO by adding 1 N sodium hydroxide solution
and extracted ~our times with 70 ml of dichloromethane
each The orgar.~ic phases obtained from the latter extrac-
tions are combined, dried, e~aporated and ~our volumes
of ethyl acetate are added to the e~aporation residue
The precipitated crystals are filtered and dried to give
3.02 g (64 0 %) of the aimed ba~e, m p : 68-70 C. After
repeated evaporation of the mo-ther liquor a~d recrystall---
zation of the residue, an additional amount of 0 55 g
(11 2 %)~of the aimed base is ob-tained
The base prepared according to ~x~mple 2 may
be trans~ormed to its hydrochloride e g as ~ollows
3.5 g of crude ranitidine are dissol~ed in
17 5 ml of absolute ethanol and the pH ~alue of this
solutio~ is adjusted to 5 to 5 5 by adding concentrated
aqueous hydrochloric acid a-t 0 C while stirring. The
mixture is stirred at 0 C for additional 40 minutes and
then set aside at 0 to ~ C o~ernight The crystalline
~Z~ L3
prec-ipi-tate is ~iltered, washed with e-thanol and clriecl
-to give 3,72 g (84.4 ~p) of the aimed hydrochloricle,
m,p,: 143 C,
nple 3
Preparation of 1-~2-[~-dirnethylaminomethyl-
-2-(furylmethylthio)-e-thy~3 -amino-l-methylamirlo-
-2-nitroethylene ~base of the formula (I)~
A solution prepared from 0~8~ g (0~00~ mole) of
silver nitrate with 10 ml of an ethanolic methylamine
solution is added to 1,66 g (0,005 mole) of 1-~2-[~-
-dimethylaminomethyl-2-(furylmethylthio)-ethy~ -amino-
-l-methylthio-2-nitroethylene ~compound of the forlnula
(IV)] suspended in 10 ml of absolute ethanol at room
1~ temperature while stirring. The mixture is stirred a-t
room temperature for additional 30 minutes, then filtered
and evaporated under reclucecl pressure, The working-up
is oarried out cLS desoribed :in ~xample 2 to giv0 1,21 g
(77,1 ~/~) of the aimed base~ 111, p, 68-70 C,
0
~xample 4
Preparatio~ of 1-~2-[~-dimethylami~omethyl-2-
-(furylmethylthio)~ethy~ -amino-l-methylamino-
-2-nitroethylene [baae of the formula (I)]
2~ A solution containing 0,8~ g (0.00~ mole) of
silver nitrate in 60 ml of allyl alcohol is portionwise
added to a solution containing 1,66 g (0,00~ mole) of
1-~2 [~-dimethylaminomethyl-2-(furylmethylthio)-ethy~ }-
~L2~;2~
~ 17 -
amino-l-methylthio-2-nitroethylene ~compou~cl of the
~orn~la (IV)~ in 20 ml of allyl alcohol wi-thin 2 -to 3
min-utes at 8 to 10 C while s-tirring, Then 8 ml of an
ethanolic methylamine solution are added at the same
temperature within 1 to 2 minutes and the mi~-ture is stirred
at room -temperature for 2 hours, The working-up is carri~d
out as described in ~xample 2 to give 0,9~ g (60,~ ~0)
of the aimed base, m,p,: 70-72 C,
F~ample ~
Control experiment
: The following control e~perimcnt was carried
ou-t in order to support that, in the process of the in-
~ention, 1-.~2-[~-dimethylaminomethyl-2-(furylmethylthio)-
1~ -ethy~ -amino-1-methylthio-2-nitroethylene [compound
of the formula (IV)] reac-ts first with silver ni-trate
~ and then, si~ultaneously with the precip-L-tation of
sil~er mothyl mercaptide, -tho thus-formed 1-~2-C~-cli-
methylaminomethyl-2-tfurylmethylthio)-othyl]~-3-nitro-
kctene:imi~e [compound of -the formula (VII)I reacts with
methylamine,
The process described in ~xample 1 was followed,
except that, after adding the sil~er nitrate, -the pre-
cipitate. formed in the solution was filtercd, washed,
2~ dried and analyzed, The precipitate weighed 2,28 g
(98,1 %)
Analysis ~or CH3AgS (molecular weight 1~4,98)
Calculated: C 7,7~ ~p; H 1,9~ ~: Ag 69,6 ~o,
Found: C 7,69 %; H 1,36 %~ Ag 69,1 %,
