Note: Descriptions are shown in the official language in which they were submitted.
:;' 1
?9U3~
! ~
~he ~res~nt -invention relates to ~ proces~ For tile pro~u(tic)n o~
4~ ethyl-5-alkylthiomethylimidazoles.
In British Patent Specification No. 1,533,380 a process
is descri~ed, according to which compounds, e.g., of the
following formula
Het-Cll2-S~c~~l2cll2~Nl~l C NHR
i are produced, wherein Elet is a heterocyclic group, e.g., an
j imidazole group, E is S or NCN, and R is H or lower alkyl,
by letting a compound of the formula
Het-CE12Z
where Het is defined as hereinbefore, and Z is a leaving group
i react with a mercaptan of the formula
Hs~cEl2cH2-NH-c~ NHRl
wherein Rlis defined as hereinbefore~
Spanish Patent Specification No. 463,839 describes the
preparation of Cimetidine, N-cyano-N'-methyl-N"-[2-[(4-methyl-
5-imidazolyl)methylthio]-ethyl]guanidine by treating 4-methyl-
5-hydroxymethylimidazole with thiourea followed by reaction
with N-cyano-N'-methyl-N"-(2-hydroxyethyl)guanidiile.
German published Specification No. 2,211,454 describes the
preparation of, e.g., Cimetidine by letting
Het-cH2-Q
wherein ~ is a leaving group, and Het is a 4-methyl-5-imida-
zolyl group, react with
IlSCH2CE12Nii2
to form
llet-CH2SCE12CE12NE12
wllich is subsequently treated with
R3Z C ~NR21
to give, e.g., Cimetidine when R is C113, R is CN, R is alkyl
or aryl and Z is S.
~ L9903~ 2
It is known that the starting materials, i.e. substituted
imidazoles, for these and other known methods are not easy
to obtain, and the present method consequently employs a
totally different approach both with regard to starting
materials and reaction pathway.
In the process according to the present invention, the
starting material consists of a compound
CH C-CCH X (I)
B
Wherein one of the substituents A and B is NOH and the other
is O or NGH. X is a suitable leaving group, e.g., halogen or
OZ, wherein Z is a hydrogen atom, or, e.g., an acyl or a tosyl
group, or X is NR3, where R is alkyl; the preferential starting
materials being the easily available halogen compounds, e.g.,
l-bromo-3-oximino-2-butanone and 4-chloro-3-oximino-2-butanone.
Compound I is treated, in a first step, with
1 ~NCN
HSAlk NH-C 2 (II~
\ NHAlk
preferably under cold conditions in the presence of a strong
base, such as sodium ethoxide, to give
~NCN
3 2Alk 2 (III)
~ \ NHAlk
A B
wherein Alk1 is an alkylene group and Alk2 is an alkyl group
having 1-4 carbon atoms.
Compounds (III) are new and constitute a further aspect of
the invention.
In a second step, the compound III is ring-closed by treat-
ment with formaldehyde or a formaldehyde donor, e.g. para-
formaldehyde, or mixtures of formaldehyde and/or formalde-
hyde donors and ammonia or ammonia donors, e.g., ammonium
acetate, or reagents with the formula
YN = CH2
~1~9~
wherein Y is HO or, preferentially, aralkyl, although other
groups may also be suitable~ to give an imidazole N-oxide
IV or V
- o
N CH2scH2cH2NH-c95 (IV)
N ~ CH3
~N ~ CH ScH2cH2NH-c~NHcH (V)
_O
~hereY isas hereinbeforedefined or H. When Y is H, the com-
pounds may consist of a mixture of two tautomers, e.g., an
N-oxide and the corresponding N-hydroxy tautomer.
The compound IV or V is subsequently selectively reduced,
if Y is other than H or OH, to reduce the Y group to H and
finally deoxygenated to give the desired product
</ ~ ~NCN
NH H SAlk -NH-C 2
which, in the preferred use of Alk1 = C2H4 and Alk2 = CH3,
is Cimetidine. The deoxygenation may also take place before
the reduction.
Compounds III were previously unknown, and since they contain
a multitude of reactive sites, it is both unexpected and sur-
prising that they can be transformed to imidazole N-oxides in
good yields. It is particularly surprising that the N-cyano-
guanidine moiety could sustain the treatment with the reagents
necessary for the ring-closure, and furthermore, according to
Zeitschrift fur Chemie, 10 (1970~,211-215, 2-unsubstituted
imidazole N-oxides cannot be isolated under reaction conditions
analogous to those used in the present invention.
The selective reduction of IV and V was unforeseeable and quite
surprising; a priori, it was to be expected that the benzylic
type C-S bond would be the one most easily reduced by known
methods.
Neither was it foreseeable that the deoxyyenation of compounds
IV and V could be undertaken, due to the number of other reactive
sites which are open for attack by known deoxygenation rea~ents,
and the use of these also led to unsatisfactory results. Sur-
prisingly, it was found that trialkylamine~sulphurdioxide com-
plexes, e.g., (CH3)3N-S02, or formamidinosulphinicacid gave the
desired product in good yield; the resulting sulphurtrioxide or
sulphonicacid would have been expected to give unwarranted side
reactions, cf. Synthesis,(1979),36.
The following examples are illustrative of the present in-
vention.
Example 1 l~irst reaction step)
N-Cyano-N'-methyl-N"-[[2-(3-oximino-2-oxobutyl)thio]ethyl]
guanidine (IIIa).
Sodium (11.0 g, 0.48 mol~ was added to ethanol (250 ml), fol-
lowed by N-cyano-N'-methyl N"-~2-mercaptoethyl)guanidine (II,
76.0 g, 0.48 mol).
To the above mixture was added, dropwise, at 20-25 C, a solu-
tion of l-bromo-3-oximino-2-butanone (86.0 g, 0.524 mol) in
anhydrous ethanol (250 ml). The reaction mixture was left at
5C over night, the precipitated sodium bromide was removed by
~iltration and the filtrate was evaporated to dryness, in vacuo.
The residue was dissolved in acetonitrile (800 ml) and stirred
with silica for 30 min., the silica was subsequently removed by
filtration, and the filtrate was evaporated, in vacuo. After tri-
turation with ether, the title compound could be isolated (99.0 g,
80%). By stirring with water and filtering, an analytically pure
sample was obtained. M.p. 111-112 C. CgH15N5O2S;
Found (Calc.): C 41.97 (42.00), H 5.90 (5.88), N 27.08 (27.22),
S 12.66 (12.46). The IR and 1H-NMR spectra are in agreement with
the given structure.
Example 2 ~first reaction step)
N-Cyano-N'-methyl-N"-[~2-(2-oximino-3-oxobutyl)thio]ethil]
guanidine (IIIb).
Sodium (5.75 g, 0-250 mol) was dissolved in ethanol (100 ml) and
added to N-cyano-NI-methyl-N''-(2-mercaptoethyl)guanidine (II,
39.6 g, 0-250 mol) in ethanol (60 ml). The resulting solution was
stirredF under nitrogen, for 1 h, and subsequently added to a
solution of 4-chloro-3-o~imino-2-butanone ~33.9 g, 0.250 mol) in
ethanol (80 ml) during a period of 40 min. at 25C. The resulting
solution was kept over night at 5C, and the precipitate isolated
by filtration followed by washing with ethanol. This product was
stirred with water for 30 min., and reisolated to give the title
compound (36.8 g, 57%) as beige-colored crystals. M.p. 133-134 C
(dec). CgH15N5O2S; Found (Calc.) C 42.15 (42.00), H 6.00 (5.88),
N 26.96 (27.22), S 12.20 (12.46). The IR and 1H-NMR spectra are
in agreement with the given structure.
3q~ 6
Example 3 (second reaction step)
N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-3-oxido-4-methylimidazol-
5-yl)methyl]thio]ethyl]guanidlne (IVa).
Compound IIIa (67.5 g, 0.262 mol) in methanol (1.0 1) was mixed
with N-benzylmethyleneimine (62.0 g, 0.521 mol) in petroleum
ether (1,0 1), and the mixture was refluxed for 72 h. The metha-
nol phase was isolated, extracted with petroleum ether, and the
solvent was evaporated, in vacuo, at 40C. The semicrystalline
residue was stirred with ether which caused fuxther crystalli-
zation, and the crystals were filtered o~f. The mother liquor
was again concentrated and once more treated with ether which
afforded a new crop of crystalline material. The combined pro-
duct was dissolved in a 1:4 mixture of methanol and chloroform,
the solution was stirred with silica, and the silica was fil
tered off. The filtrate was concentrated, in vacuo, the residue
stirred with acetonitrile, and the resulting cr~stals were
filtered off and washed with ether to give the title compound
(66.0 g, 70%). M.p. 186-187 C (dec). C17H22N6OS; Found (Calc-)
C 56.56 (56.95), H 6.17 (6.19), N 23.23 (23.45) S B.7~ (8.95).
The IR, lH-NMR and 13C-NMR spectra are in agreement with the
gi~en structure.
Example 4 (second reaction step)
N-Cyano-N'-methyl-N"-~2-~[~1-benzyl-3-oxido-4-methyl imida~ol-
5^yl)methyl]thio]ethyl]guanidine (IV a).
N-Cyano-N'-methyl-N"-[[2-(3-oximino-2-oxobutyl~-thio]ethyl~
guanidine (III a) (12.9 g, 50 mmol~in methanol (60 ml) was
mixed with N-benzyl methylene-imine (9.0 g, 75 mmol) and acetic
acid (o.6 g, 10 mmol) and stirred at 25Cfor 13 h. The solvent
was evaporated in vacuo, at 60C-The resulting residue was
heated to reflux with acetone ~100 ml) for 30 min. whereby
crystallization occured. After cooling to 10C the crystals
were filtered off and dried to give the title compound !15.2 g,
85%). M.p.1~3-1~4QC (dec.).
~9~ 7
Exam~le 5 (second reaction step3
N-Cyano-N'-methyl-N"-[2-[[(1-ben~yl-3-oxido-5-methylimidazol-
4-yl)methyl]thio]ethyl]guanidine (Va).
Compound III b (2.57g, 0.010 mol)in methanol (25 ml) was mixed
with N-benzylmethyleneimine (2.38 g, 0.020 mol3 and heated under
nitrogen to reflux for 17 h. The resulting solution was evapo-
rat~d to dryness in vacuo, and the residue was crystallized from
acetonitrile to give the title compound (2.87 g, 80%, m.p. 178-
180 C (dec)- C17H22N6OS; Found (Calc.) C 5G.77 (56i96), H 6.20
(6.19),N 23.61 (23.45), S 9.03 (8.95). The IR and H-NMR spectra
are in agreement with the structure given.
Example 6 (removal step)
N-Cyano-N'-methyl-N"-[2[[(1-oxido-5-methylimidazol-4-yl)methyl]
thio]ethyl]~uanidine (IVb).
Compound IVa (35.0 g, 0.0976 mol) was suspended in li~uid ammo-
nia (700 ml) and sodium (7.2 g, 0.31 mol) was added, followed
by ammonium chloride (16.7 g, 0.31 mol). The ammonia was subse-
quently removed by heating to room temperature, anhydrous alco-
hol (200 ml) was added, and the reaction mixture was stirred
for 30 min. and filtered. The filtrate was concentrated, in vacuo,
the residue was washed with ethyl acetate, the ethyl acetate
phase was decanted off, and the resulting residue crystallized
from methanol to give the title compound ~15.3 g, 58~). M.p.
161-162 C. CloH16N6OS; Found (Calc.) C 43.65 ~44O75)~ H 6.00
(6.01), N 30.86 (31.32),S 12.02 (11.95). The IR H-NMR and
C-NMR spectra are in agreement with the given structure.
(removal step3
N-Cyano-N'-methyl-N"-[2-[[(1-oxido-4-methylimidazol-5-yl3methyl]
thio]ethyl]guanidine ~Vb).
Compound IVb(3.59, 10~0 mmol) was dissolved in liquid ammonia
(100 ml), and sodium (0.53 g, 23 mmol) was added in small por-
tion~, ~ollowed by ammonium chloride (1.23 g 23 mmol)~ The
ammonia ~as removed by heating to room temperature, propanol
was added, the formed suspension was stirred for 30 min and
filtered. The fil~rate was seeded with crystals of Vb and cooled.
The precipitated crystallin~ material was filtered off and dried
to gi~e the title compound (2.0 g, 75~). M.p. 176-178C (dec)~
Recrystalli~ation from dry methanol raised the m.p. to 180-183C
ldec). C1oH16N6OS; Found (Calc.) C 44.62 (44.75), H 5.96 (6.01),
N 31.24 (31.32), ~ 98 (11.95). The IR and H-NMR spectra are
in agreement with ~he given structure.
Example 8 (second reaction step - IIIb > Vb direct)
Compound Vb.
Compound IIIb (2.57 g, 10.0 mmol), ammonium acetate (1.15 g,
15.0 mmol) and paraformaldehyde (0.33 g, 11.0 mmol) in 2 N
acetic acid (20 ml) were stirred for 2 h at 65C. HPLC indicated
a yield of 72~ of the title compound. The solvent was removed in
vacuo, and the residue adjusted to pH 8 with 3 N potassium hydro-
~ide. The solvent was removed in vacuo, and the residue was dis-
solved in chloroform-methanol (4:1) followed by stirring with
silica and filtration. The filtrate was evaporated, in vacuo, and
the residue was crystallized from methanol to give 1.20 g of Vb,
H2O. The mother liquor yielded a further crop of Vb, H2O (0.51g)
by chromatography on silica gel. Total yield of crystalline Vb,
H2O was 60~. C10H16N6OS, H2~; Found (Calc.) C 41.70 (41.94), H 6-19
(6.3~), N 29.42 (29.35), S 11.25 (11.20), H2O 6.33 (6.29). Recry-
stallization from dry ethanol raised the m.p. to 181-183C (dec).
The compound was identical with an authentic sample (IR and H-~MR
spec-troscop~
Example 9 (second reaction step - IIIb ` Vb direct)
Compound V~.
Compound IIIb (5.15 g, 20.0 mmol~, ammonium dihydrogenphosphate
t2~30 g, 20.0 mmol), ammonium hydrogenphosphate (1.32 g, lO.0 mmol)
and paraformaldehyde (0.72 g, 24 mmolj in water (40 ml) were
stirred for 2 h at 65C, after which time, HPLC analysis showed
a content of 57~ of compound Vb. The reaction mixture was adjusted
to pH 8 with aqueous ammonia and the solvent was removed, in vacuo.
The residue was chromatographed on silica gel with chloroform-
methanol (3:1~ as eluent. The main fraction from this was crystal-
lized from methanol to give 2.73 g (48~) of Vb, H2O.
Example10 (second reaction step - IIIb ~ Vb direct)
Compound Vb.
Compound IIIb (3.86 g, 15.0 mmol), ammonium acetate (1.61 g, 21.0
mmol) and paraformaldehyde (0.63 g, 21.0 mmol) in acetic acid (40 ml)
was stirred for 10 h at rcom temperature, the solvent was removed,
in vacuo, and the residue chromatographed on silica with chloro-
form-methanol (3:1) as eluent. The main fraction was crystallized
from methanol to give Vb, H2O (1.71 g, 41~), identical by IR and
1H-NMR with an authentic sample.
Example 11 (second reaction step - IIIa ~ IVb)
Compound IVb.
Compound IIIa (2.57 g, lO.0 nmol), ammonium acetate ~1,15 g,
11.0 mmol) and paraformaldehyde (0.33 g, 11.0 mmol) in 2 N acetic
acid (20 ml) were stirred for 2 h at 65 C, after which time,
HPLC analysis showed a content of 40% of IVb. The solvent was re-
moved, in vacuo, and the residue was adjusted to pH 8 with 3 N
potassiun hydroxide, followed by renewed evaporation, in vacuo.
The residue from this was chromatographed on silica gel with
chloroform-methanol (3:1) as eluent. The main fraction was cry-
stallized from methanol to give 0.68 g (25%) of IVb.
Example 12 (deoxydation step)
N-Cyano-N'-methyl-N"-[2-[[4-methylimidazol-5-yl)methvl]thio]
ethyl]guanidine (Cimetidine~.
Compound IVb (3.00 g, 11.2 mmol) and trimethylamine-sulphur
dioxide ((CH3)3N~SO2, 2.7 g, 22 mmol) in methanol (60 ml)
was heated to 130C for 5 h in an autoclave. After cooling, the
reaction mixture was concentrated, in vacuo. Water (6 ml), and
~ ~ 10
potassium carbonate (2.0 g, 14.5 mmol) was added, which permitted
the isolation of an almost quantitative yield of crude Cimetidine
(2.83 g, m.p. 136-138 C). After recrystallization, the m.p. was
raised to 142-143 C. CloH16N6lS; Found (Calc.) C 47.60 (47.60),
Il 6.42 (6.39), N 32.94 (33.31), S 12.81 (12.71). The I~ and
lHNMR spectra are identical to those of an authentic sample.
Example 13 (deoxydation step)
Cimetidine.
Compound IVb (121 mg, 0.45 mmol) was dissolved in dimethylfor-
mamide (~.8 ml), formamidinosulfinic acid ((H2N)2C-SO2, 49 mg,
0.45 mmol) was added, and the mixture was heated to 100C for
1 h, after which it was shown to contain 48~ Cimetidine ~y
HPLC.
~xample 14 (deoxydation step)
Cin~eLidine.
Compound IVb (2.00 9, 7.5 mmol) was dissolved in '-ethox,ethanol
(40 ml), trime~hylammonium sulfinate (2.70 ~, 21.9 mmol) was
added~ and the mixture was ~leated to reflux for 15 min. Su~se-
quently, analysis by }IPLC revealed the presence of 72~ Cimeti-
dine, of which 1.30 g, 69%, could be isolated.
Example 15 (deoxydation step~
Cimetidine.
Compound Vb was deoxyc;enated analogously to the method described
in Example 11to qive Cimetidine.
l~lLg'90~ 0 11
Example 16 (deoxydation of V before removal of the benzyl group)
N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-5-methyl imidazol-4-yl)
methyl~thio]ethyl]guanidine (A).
N-Cyano-N'-methyl-N"-[2-[[(1-benzyl-3-oxido-5-methyl-imidazol
-4-yl)methyl]thio]ethyl]guanidine (V~ l7,2 g, 20 mmol) was
heated to reflux with 1.7M trimethylamine-~ulphur d1oxide in
ethanol (24 ml) for 16 h. After cooling toO C,the crystals
were filtered off and dried to give the title compound (6.2 g,
91~). M.p.178-179 C.C~7~l22N6S; Found (Calc.) C 59.53 (59.~2),
H 6.55 (6.48), N 24.43 (24.54), S 9.41 (9.36). The 'H-NM~ and
3C-NMR spectra are in agreement with the given structure.
Example 17 (deoxydation of IVa before removal of the benzyl group~
N-Cyano-N'-methyl-N"-~2-~[(1-benzyl-4-methyl imidazol-5-yl)
methyl]thio]ethyl]guanidine (B) Method I.
N-Cyano-N'-methyl-N"-[2-~[(1-benzyl-3-oxido-4-methyl-imidazol
-5-yl)methyl~thio]ethyl]guanidine (IV a) ~17.9 g, 50 mmol) wa~
heated to reflux with 1.7M trimethylamine-sulphur dioxlde in
ethanol (60 ml) for 5 h. After cooling to 0C,the crystals were
filtered off and dried to give the title compound (14.9 g, 87~).
M.p. 173-175 C.
C17~22N6S; Found (calc.) C59.81 (59.62), H 6.44 (6.48), N 24.83
(24.54), S 9.42 (9.36). The 'H-NMR and 13C-NMR spectra are in
agreement with the given structure.
0~
Example 18
~B) Method II.
Compound IV a (3.58 g, 10 mmol) was dissolved in methanol
~50 ml) and added 5~ Palladium on carbon (0.36 g). The mixture
was stirred in an atmosphere of hydrogen (1 atm) for 3 days at
room temperature.
The catalyst was filtered off. The filtrate was evaporated to
dryness, to the residue was added acetone (60 ml) and heated
to reflux. After cooling to room temperature the crystals wers
filtered off and dried to give the title compound (3.05 g, ~9~).
M.p. 172-175C.
Example 19 (removal of the benzyl group)
N-Cyano-N'-methyl-N"-[2-[[(4-methyl imidazol-5-yl)methylj
-thio~ethyl]guanidine (Cimetidine).
Compound B (274 g, 0.80 mol) was suspended in liquid ammonia
(1200 mll. Sodium (40.0 g, 1.74 mol) was added, followed by
ammonium chloride (93.1 g, 1.74 mol) dissolved in water
(400 ml). Excess of ammonia was allowed to evaporate. The
resulting suspension was filtered. The precipitate was dried
to give the title compound (185 g, 92%). M.p. 138-141C.
HPLC indicated a purity of 97%.
