PROCESS FOR THE PREPARATION OF A FURAN DERIVATIVE

PREPARATION D'UN DERIVE DE FURANE

English Abstract

ABSTRACT
Process for the Preparation of a Furan Derivative
Ranitidine is prepared by treating the compound
(II)
<IMG>
(II)
in which R represents H or preferably methyl with
a methylating agent such as a methyl halide, dimethyl
sulphate or a methyl sulphonic ester. The reaction
may be carried out in the presence of a base or an
alkali metal methylsulphinylmethide salt. The starting
material (II) is readily obtainable in pure crystalline
form and the process does not involve evolution of
thiol.

Claims

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 ranitidine
of the formula (I)
<IMG> (I)
which comprises treating a compound of the general
formula (II)
<IMG> (II)
in which R represents a hydrogen atom or a methyl group,
with a methylating agent.
2. A process as claimed in claim 1 in which R
represents a methyl group.
3. A process as claimed in claim 1 or 2 in which
the methylating agent is a methyl halide, dimethyl
sulphate or a methyl sulphonic ester.
4. A process as claimed in claim 1 carried out in
the presence of a base.
5. A process as claimed in claim 4 wherein the base
is sodium carbonate, potassium carbonate, sodium
bicarbonate, postassium bicarbonate, pyridine or triethyl
amine.

6. A process as claimed in claim 1 carried out in
the presence of an alkali metal methylsulphinyl methide
salt.
7. A process as claimed in claim 6 in which the
alkali metal methylsulphinylmethide salt is prepared
in situ from an alkali metal hydride and dimethylsulphoxide.
8. A process as claimed in claim 1, claim 2 or
claim 4 carried out at a temperature of 0 to 50°C.
9. A process as claimed in claim 1 in which the
furan derivative of formula (I) is subsequently converted
into an acid addition salt.
10. A process as claimed in claim 9 in which the
acid addition salt is the hydrochloride.

Description

~3~
Proces__For the Preparation of a furan derivative
_ _ .
This invention relates to a process for the
preparation of a furan derivative.
The furan derivative of formula (I)
t~
/~ 1CI~Nn2 (I)
Me2NCH2 0 CH2SC~2CH2NHCNHMe
which is known as ranitidine is disclosed in ~ritish
Patent Specification No. 1565966 as a potent and selective
H2- antagonist.
lOThe present invention provides a novel and useFul
process for the preparation of ranitidine of formula (I)
which comprises treating a compound oF formula (II)
15RHNCH2 CH2SCH2CH2NHCNHMe (II)
in which R represents a hydrogen atom or a methyl qroup
with a methylating agent. Suitable methylating agents
include methyl halides such as methyl bromide or methyl
iodide, di~ethylsulphate or Methyl sulphonic esters such
as methyl methanesulphonate or methyl p-toluene-
sulphonate.
The reaction may optionally be carried out in the
presence of a base or a salt such as an alkali metal
methy1sulphinylmethide.

- 2 - ~ ~37~
Suitable bases include carbonates e.~. sodium
carbonate or potassium carbonate, bicarbunates e.g. sodium
bicarbonate or potassium bicarbonate or organic bases such
as pyridine or triethylamine.
When the reaction is carried out in the presence of a
base the compound of formula (II) may conveniently be used
in the form of an acid addition salt such as a
hydrochloride salt.
When the reaction is carried out in the presence of an
alkali metal methylsulphinylmethide salt, such as the
potassium salt or more particularly the sodium salt,
NaCI-12S(O)CH3, this is conveniently prepared in situ from an
alkali metal hydride such as sodium hyclride and
dimethylsulphoxide.
When the compound of formula (II) is reacted ~lith the
methylating agent alone or in the presence of a base, the
reaction may be carried out in an aprotic solvent such as
an amide eg dimethylformamide or N-methylpyrrolidone, or
acetonitrile, or an alcohol e.g. methanol or ethanol, or
a ketone eg methyl ethyl ketone. ~lternatively, when an
organic base is used, this may conveniently also be
employed as the solvent for the reaction.
The reaction involvinq the alkali metal methyl-
sulphinylmethide salt may also he carriecl out in the
presence of a solvent, suitàble solvents includinq
dimethylsulphoxide or an ether eg tetrahydrof~lran.

~ 3 - ~ ~3~4~
rhe methylation reaction is conveniently carried out
at a temperature of from 0 to 50, preferably at room
temperature.
A preferred process according to the present
invention involves preparing ranitidine of formula (I) by
methylating a compound of formula (Il) in which R
represents a methyl group.
If desired the furan derivative of formula (I) once
obtained may be converted into an acid addltion salt, eg a
hydrochloride, using conventional methods. Thus for
example, appropriate quantities of the free base of
formula (I) and an acid, eg hydrochloric acid, may be
mixed in a suitable solvent(s), eq an alcohol such as
sthanol or isopropanol, or an ester such as ethyl acetate.
The process of the present invention is advantageous
- in that the starting material of formula (II) is readily
obtainable in a pure crystalline form. Furthermore, the
process has the advantage that there is no evolution of
thiol. This is a significant advantaqe since it is
necessary to prevent the release of thiol into the
environment and this requires the use of specialised
equipment which is expensive to run.
The invention is illustrated but not limited by the
followinq examples in which temperatures are in C and
hplc refers to hiqh perFormance liquid chromato~raohy.

3~49L~
-- 4
Example 1
N-[2-[[5-[(Dimethylamino)methy1]-2-furanylmethyl]thio]
ethyl] -N'-methyl-2-nitr:o-1 7?-ethenediamine
(a) A mixture of sodium hydride (70O dispersion in oil,
0.159) and dry dimethylsulphoxide (30ml) was heated at
70-75 for 0.75h under nitrogen. On cooling to 20 a
solution oF N-[2-[[5-[(methylamino)methyl]-2-Furanyl-
methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ether1ediamine
(1.2~) (Compound A) in dimethylsulphoxide (10ml) was added
dropwise fnllowed by the addition of iodomethane (0.27ml)
in dimethylsulpho`xide (10ml) and the so]ution was stirred
at 20, under nitrogen, for 18h. Water (10ml) was added
and the mixture was evaporated in vacuo. The residue was
partitioned between dichloromethane (50ml) and 2N aqueous
sodium carbonate (50ml). The dichloromethane layer was
separateo and the aqueous layer further extracted with
dichloromethane (2x50ml). The combined dichloromethane
extracts were washed with brine, dried (Na2C03) and
evaporated and the residue (1.59) was chromatographed on
2b silica [~lerck No. 7734, 809] using dichloromethane:
ethanol:O.88 ammonia 75:n:1 as eluent to qive the title
(0.179). N.m.r. and I.r. spectroscopy showed
that this sample was consistent with the title compound

374~L~
prepared according to the method oF Example 15 in British
Patent Specification No. 1565966.
(b) Similarly, sodium hydride (60o dispersion in oil,
0.449), dimethylsulphoxide (60ml), Compound A (1.5g) and
methyl tosylate (1.02g) gave a product which was shown by
hplc to contain about 157mg of the title compound.
(~) Similarly, sodium hydride (60no dispersion in oil,
- 0.449), dimethylsulphoxide (80ml), Cornpound A (1.59) anrl
dimethylsulphate (0.76ml) gave a product which was
shown by hplc to contain about 157mg of the title
compound~
Example 2
N-[2-[[[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]-
ethyl]-N'-methyl-2-nitro-1,1-ethenediamine
(a) N-[2-[[[5-[(methylamino)methyl]-2-furanyl~methyl~-
thio] ethyl]-N'-methyl-2-nitro-1,1-ethenediamine
hydrochloride (Compound B) (1.33g) and potassium carbonate
(0.559) in methanol (25ml) were treated with iodomethane
~0 (0.5~9) at 0-4 for 5h and then at room temperature for a
further 17h. The reaction mixture was stlown by hplc to to
contain 211mg of the title compound.

~2~7~
(b) Similarly, Compound 8 ~0.54g), triethylamine (0.339),
methanol (12ml) and iodomethane (0.1ml) gave a mixture
which was shown by hplc to contain about 50mg o~ the title
compound.
(c) Similarly, Compound B (0.54q), pyridine (0.199),
methanol (12ml) and iodomethane (0.1ml) gave a mixture
which was shown by hplc to contain about 50mq of the title
compound.
(d) Similarly, Compound A (0.549), methanol (12ml) and
iodomethane (0.1ml) gave a mixture which was shown by hplc
to contain about 50mg of the title compound.