Note: Descriptions are shown in the official language in which they were submitted.
~73~5~
This invention relates to a process for the manufacture
of a valuable chemical intermediate.
Pd ~1~07&, & p~L/~h~ /Jo~J4n~b~r ~
~ In German Patent Application ~ ~17078.8 there is tq7~
,
described the preparation of histamine H-2 antagonists, which
are useful in the treatment of peptic ulcers and other related
conditions, using dimethyl and diethyl (N_cyanoimido)carbonates.
Other histamine H-2 antagonists, such as those described in
Belgian Patent 866155 and European Patent Publications 0003640,
0006286 and 0006679, as well as those described in, for example,
United Kingdom Patents 1,338,169 and 1,397,436, may be prepared
using the same intermediates. The preparation of dimethyl
(N-cyanoimido)carbonate from dimethyl (N-cyanoimido)dithiocarbonate
is described in J.Org.Chem., 1974, 39, 1522. The preparation of
diethyl (N-cyanoimido)carbonate by reaction of diethyl imido-
carbonate with cyanamide in a non-aqueous solvent at OC is
described in Chem Ber., 1967, 100, 2604.
The preparation of diethyl imidocarbonate from cyanogen
chloride by reaction with anhydrous ethanol and sodium ethoxide
at -10C. is described in Annalen, 1895, 287, 310. When water, or
a temperature above O, was used by-products were formed. The
product was also difficult to isolate when water was used.
It has now been discovered that these compounds may be
prepared, in high yield and in pure form, by reaction of the
appropriate imidocarbonate with cyanamide under aqueous conditions,
and that the imidocarbonate itself can be prepared ~rom cyanogen
chloride or bromide and the appropriate alcohol or diol under
similar conditions.
~'
~3C~O
According to the invention, a disubstituted imidocarbonate
of the formula
R10
\ C=NH II
R2 o /
in which Rl and R2 are the same and are alkyl radicals of 1 to 6
carbon atoms or phenyl radicals, or Rl and R2 are joined to form
an ethylene or propylene chain which is optionally substituted by
1 or 2 alkyl radicals each of 1 to 3 carbon atoms, may be manu-
factured by reaction of cyanogen chloride or cyanogen bromide with
the appropriate alcohol or diol in a two phase system containing
water and a water-immiscible organic solvent. The reaction is
preferably conducted in the presence of a base. When Rl and R2 are
alkyl or phenyl radicals, the cyanogen chloride or cyanogen bromide
is preferably reacted with two or more molecular equivalents of an
alcohol of the formula Rl-OH in the presence of slightly more than
one equivalent of a base. When Rl and R2 are joined, the cyanogen
chloride or cyanogen bromide is reacted with one or more molecular
equivalents of diol in the presence of slightly more than one
equivalent of base. The base used may be in the form of an
alkoxide derived from the alcohol or diol employed in the
subsidiary process of the invention. When so used, the minimum
amount of free alcohol or diol required is reduced by an amount
equivalent to the amount of alkoxide used. Alternatively the
base may, for example, be an alkali or alkaline earth metal
hydroxide such as sodium or potassium hydroxide. A preferred base
is sodium hydroxide. The alcohol and/or the base may be used in
amounts considerably in excess of the minimum amounts quoted
1~7~3~50
above. Thus, for example, when Rl and R2 are alkyl or phenyl
radicals, from 2 to 10, and preferably from 3 to 4, molecular
equivalents of alcohol Rl-OH may be used, and from ~1.0 to 5,
and preferably 1.1 to 1.5, equivalents of base may be used.
When Rl and R2 are joined, the number of molecular equivalents
of diol which may be used is from 1 to 5, and preferably from 1.5
to 2. The base is preferably present in such amount that the pH
of the reaction medium in the subsidiary process is in the range
11 to 15. The process may be conducted at a temperature in the
range -15 to 60C., and preferably in the range -5 to 25C. A
particularly preferred temperature $S in the range 5 to 25 C.
The water-immiscible organic solvent is, for example, an alkyl or
dialkyl benzene in which the alkyl radicals are of 1-6 carbon
atoms, for example toluene, xylene or ethylbenzene, or methylene
chloride, ether, chloroform, chlorobenzene, n-butanol or
isobutanol. A preferred water-immiscible organic solvent is
toluene. A solvent which is unstable to base, for example ethyl
acetate, cannot be used. If an alcoholic solvent is used, it
must be the same alcohol or diol as that which participates in
the reaction. The process may be conducted over a period of
between 5 minutes and 24 hours, and preferably over a period of
between 30 minutes and 10 hours. The process enables the
disubstituted imidocarbonate to be obtained in high yield and
in substantially pure form.
At the completion of the process of the invention, the
pH of the reaction mixture may be lowered by the addition of a
strong mineral acid such as hydrochloric or sulphuric acid, to the
1~73[DSO
preerred pH range for converting the imidocarbonate into the
corresponding N-cyanoimido-carbonate. That process may be eff0cted
by reaction of the disubstituted imidocarbonate of formula II with
cyanamide, the reaction once again being conducted in a two phase
system containing water and a water-immiscible organic solvent.
The process may be conducted at a temperature in the
range -15 to 60C., and preferably at a temperature in the range
-5 to 25C. A particularly preferred temperature is in the range
5 to 25C.
The process may be carried out over a period of from 5
minutes to 24 hours, and preferably over a period o~ 5 minutes to
1 hour. The cyanamide may be used as the free base or as a salt
such as the hydrochloride, hydrobromide, dihydrochloride or dihydro-
bromide. The dihydrochloride or dihydrobromide may be used in the
solid form, as such, or the hydrochloride, hydrobromide, dihydro-
chloride or dihydrobromide may be used in the form of an aqueous
solution. Alternatively, any one of these salts may be prepared
n situ in the reaction mixture.
The product may be isolated by separation of the water-
immiscible solvent from the aqueous layer, optionally followed by
a further extraction of the aqueous layer with a water-immiscible
organic solvent. The product may be isolated by evaporation of
the organic solvent to dryness, or the product may be precipitated
by addition of an organic solvent in which the product has very low
solubility, for example petroleum ether or hexane. Such an addition
may be made after an optional reduction in the volume of the water-
immiscible organic solvent. The precipitation of the product
~7~6~S0
may be encouraged by cooling the solvent mixture, for example to
0C. The product may, if necessary, be recrystallised from a
solvent such as a mixture of methylene chloride and ether, or a
mixture of toluene and hexane.
A preferred pEI for this reaction is in the range 4 to 10,
and a particularly preferred pH is in the range 5 to 8.
The invention is illustrated, but not limited, by the
following Examples in which Example 3 illustrates a preferred
process.
Example 1
A concentrated aqueous sodium hydroxide solution was
prepared by dissolving sodium hydroxide (46 g,) in water(53 ml.).
A weighed amount of this solution (58.6 g., containing 27.1 g.,
0.677 moles, of sodium hydroxide) was diluted with water 20 ml.)
and the diluted solution was added to a mixture of methanol (54.2
g., 1.69 moles) and toluene (90 ml.) with stirring at 0-5C. A
solution of cyanogen chloride (34.7 g., 0.564 moles) in toluene
(25 ml.) was added over 1 hour, the temperature of the reaction
mixture being maintained at 0-5C, and the mixture was then
stirred for a further 2 hours at 0-5C. Concentrated hydrochloric
acid (61.5 g. of a solution prepared by adding 36 g. of HCl to 64
ml. of water, equivalent to 22.2 g. 0.609 mole, of HCl) was then
added, keeping the temperature below 5C, until the pH of the
reaction mixture had fallen to 7 (about 13 ml. of the acid having
been added). An aqueous solution of cyanamide (42.3 g. of a
i~L73~50
solution prepared by dissolving 50 g. of cyanamide in 50 ml. of
water, equivalent to 21.2 g, 0.508 mole, of cyanamide) was then
added simultaneously with the remainder of the acid. The temper-
ature of the mixture was then raised to 20C over 1 hour. Water
(40 ml.) was added and when all the sodium chloride had dissolved,
the layers were separated~ The aqueous layer was extracted with
toluene (2 x 50 ml.) and the combined toluene solutions were
washed with saturated aqueous sodium chloride (2 x 15 ml.) and
evaporated to give dimethyl(N-cyanoimido)carbonate (47.1 g., 73.3%)
as a white solid. Alternatively, the product was isolated by con-
centrating the combined toluene solutions to about 30 ml. and
adding about 40 ml. of hexane. The product had m.p. 52-64C on
recrystallisation from methylene chloride/ether 1:2 v/v. The
melting point reported in J. Org. Chem., 1974, 11, 1524, is 52-56C.
Example 2
Cyanogen chloride (8.67 g.; 0.141 moles) was dissolved
in absolute ethanol (33 ml.; 0.57 moles) with stirring. Toluene
(37.5 ml.) was added and the solution was cooled in an ice/salt
bath to -10C. A solution of sodium hydroxide (11.24 g.; 0.281
moles) in water (29 ml.) was added over 1 hour, maintaining the
temperature at -10 to -5C. The reaction mixture was then stirred
at -5C. for a further 1 hour. Concentrated hydrochloric acid 36%
w/w (23.0 g. - 8.28 g. HCl, 0.227 moles) was added dropwise, main-
taining the temperature at -5C., and when half of the acid had
been added a solution of cyanamide (4.74 g.; 0.113 moles) in water
(4.7 ml.) was added simultaneously with the remainder of the acid.
The total time for the addition was 40 minutes and the final pH was
1~73~SO
6-7. ~he cooling bath was removed and the reaction mixture was
allowed to warm to room temperature over 30 minutes. The toluene
layer was separated and the aqueous solution was extracted with
ethyl acetate (2 x 50 ml.). The organic solutions were combined,
washed with water (3 x 25 ml.), dried (MgSO4) and evaporated to
give diethyl (N-cyanoimido)carbonate (10.19 g.; 51%) as a yellow
oil. The infra-red spectrum (liquid film) of the product was
identical to that described in Chem. Ber. 1967, 100, 2604.
Example 3
A mixture of toluene (300 ml.) and methanol (120 g.,
3.75 g. moles) was stirred and cooled to 10-15C. A solution of
sodium hydroxide (45.1 g., 1.13 g. moles) in water (50.9 ml.) was
added to the mixture keeping the temperature below 15C. Cyanogen
chloride (58.0 g. 0.94 g. moles) was then passed into the reaction
vessel at such a rate as to maintain the temperature in the range
0-15C. After this addition the mixture was stirred for 2 hours
during which time the temperature was lowered to -10 to -5C.
Concentrated hydrochloric acid (19.0 g. of a solution prepared by
adding 36 g. of HCl to 64 ml. of water, equivalent to 6.8 g.,
0.19 g. mole, of HCl) was then added over about 10 minutes after
which the pH of the reaction mixture was 8-9. Without delay a
mixture of an aqueous solution of cyanamide (63 g. of a solution
prepared by dissolving 50 g. of cyanamide in 50 ml. of water,
equivalent to 31.5 g., 0.75 g. mole, of cyanamide) and concentrated
hydrochloric acid (72.5 g. of a solution prepared by adding 36 g.
of HCl to 64 ml. of water, equivalent to 26.0 g., 0.71 g. mole, of
HCl) was added over about 10 minutes keeping the temperature of
~73~SC~
the reaction mixture below 15C. The pH of the mixture at the end
of the addition was about 6. The mixture was warmed to 20-25C.
and stirred at that temperature for 1 hour. Water (120 ml.) was
added to this reaction mixture to dissolve the sodium chloride
and the layers were separated. The aqueous solution was extracted
with more toluene (2 x 90 ml.). The three toluene solutions were
combined and washed with a solution of sodium chloride (14 g.) in
water (41 ml.). The toluene solution was stirred and diluted with
cyclohexane (500 ml.) and the mixture was then stirred at -5 to 0C.
for 2 hours. Filtration afforded dimethyl(N-cyanoimido)carbonate
(58.1 g., 54%) as a white crystalline solid which was washed with
cyclohexane (100 ml.) and dried in vacuo at 20C.
Example 4
A concentrated aqueous sodium hydroxide solution was pre-
pared by dissolving sodium hydroxide (46 g.) in water 53 ml.).
A weighed amount of this solution (87.7 g., containing 40.8 g.,
1.02 g. moles, of sodium hydroxide) was diluted with water (29 ml.)
and the diluted solution was added to a mixture of methanol (67.7
g., 2.11 g. moles) and toluene (125 ml.) with stirring at 0-5C.
20 A solution of cyanogen chloride (32.5 g., 0.53 g. moles) in toluene
~25 ml.) was then added maintaining the temperature of the reaction
mixture below 5 C. The mixture was stirred at 0-5C. for 1 hour
then water (50 ml.) was added and stirring was continued at 0-5C.
for a further 2 hours. Concentrated hydrochloric acid (96.4 g. of
a solution prepared by adding 36 g. of HCl to 64 ml. of water,
equivalent to 34.7 g., 0.95 g. mole, of HCl) was added over 30
minutes keeping the temperature below 5C. and then an aqueous
1~73~S~)
solution of cyanamide (40.7 g. of a solution prepared by dissolv-
ing 50 g. of cyanamide in 50 ml. of water, equivalent to 20.4 g.,
0.49 g. mole, of cyanamide) was added over 2 minutes at 2C. The
mixture was stirred at 20-25C. for 30 minutes and the layers were
separated. The aqueous layer was extracted with toluene (2 x 50
ml.). The toluene solutions were combined, washed with saturated
aqueous sodium chloride solution (2 x 15 ml.) and evaporated to
give dimethyl (N-cyanoimido)carbonate (20.3 g., 33%) was a white
solid.
Example 5
A concentrated aqueous sodium hydroxide solution was
prepared by dissolving sodium hydroxide (46 g.) in water (53 ml.).
A weighed amount of this solution (91.3 g. containing 42.4 g.,
1.06 g. moles, of sodium hydroxide) was diluted with water (30 ml.)
and the diluted solution was added to a mixture of methanol (70.4
g., 2.2 g. moles) and toluene (125 ml.) with stirring at 0-5C.
A solution of cyanogen chloride (33.8 g., 0.55 g. moles) in toluene
(25 ml.) was then added, maintaining the temperature of the
reaction mixture below 5C. The mixture was stirred at 0-5C. for
1 hour then water (50 ml.) was added and the mixture was stirred
at 0-5C. for a further 2 hours. Concentrated hydrochloric acid
(53.0 g. of a solution prepared by adding 36 g. of HCl to 64 ml.
of water, equivalent to 19.1 g., 0.52 g. mole, of HCl) was added,
keeping the temperature at 0-5 C., to give a pH of 8. An aqueous
solution of cyanamide (42.4 g. of a solution prepared by dissolv-
ing 50 g. of cyanamide in 50 ml. of water, equivalent to 21.2 g.,
0.5Q g. mole, of cyanamide~ was added quickly and then more con-
~73~50
centratedhydrochloric acid (47.2 g. of solution, equivalent to17.0 g., 0.47 g. mole, of HCl) was added keeping the temperature
at 0-5C. The mixture was stirred for 30 minutes at 20-25C. and
the layers were separated. The aqueous layer was extracted with
toluene (2 x 50 ml.). The toluene solutions were combined, washed
with saturated aqueous sodium chloride solution (2 x 15 ml.) and
evaporated to give dimethyl (N-cyanoimido)carbonate ~27.8 g., 44~)
as a white solid.
Example 6
-
A concentrated aqueous sodium hydroxide solution was
prepared by dissolving sodium hydroxide (46 g.) in water (53 ml.).
A weighed amount of this solution (70.5 g., containing 32.8 g.,
0.82 g. mole, of sodium hydroxide) was diluted with water (24 ml.)
and the diluted solution was added to a mixture of methanol (54.4
g., 1.70 g. mole) and toluene (125 ml.) with stirring at 0-5 C.
A solution of cyanogen chloride (26.1 g., 0.42 g. mole) in toluene
(45 ml.) was added over 30 minutes maintaining the temperature at
0-5C. and the mixture was stirred at 0C. for 90 minutes. Water
(50 ml.) was then added, followed by concentrated hydrochloric acid
(41.0 g. of a solution prepared by adding 36 g. of HCl to 64 ml.
of water, equivalent to 14.8 g., 0.40 g. mole, of HCl) which was
added all at once. The temperature rose to 27C. and the pH was 8.
An aqueous solution of cyanamide (32.7 g. of a solution prepared by
dissolving 50 g. of cyanamide in 50 ml. of water, equivalent to
16.4 g., 0.39 g. mole, of cyanamide) and more concentrated hydro-
chloric acid (36.4 g. of solution, equivalent to 13.1 g., 0.36 g.
mole, of HCl) were added simultaneously to the mixture over 5
--10--
~7305(~
minutes. The temperature of the mixture rose to 38C. and the
final pH was 6. The mixture was stirred for 30 minutes at 20-25 C.
and the layers were separated. The aqueous layer was extracted
with toluene ~2 x 50 ml.). The toluene solutions were washed with
saturated aqueous sodium chloride solution (2 x 15 ml.) and
evaporated to give dimethyl (N-cyanoimido)carbonate (32.5 g., 67%)
as a white solid.
Example 7
A concentrated aqueous sodium hydroxide solution was
prepared by dissolving sodium hydroxide (46 g.) in water (53 ml.).
A weighed amount of this solution (51.5 g., containing 23.9 g.,
0.60 g. moles, of sodium hydroxide) was added to a mixture of
methanol (56.9 g., 1.78 g. moles) and toluene (150 ml.) over 12
minutes with stirring at 15-20C. The mixture was warmed to 40C.
and then a solution of cyanogen chloride (31.0 g., 0.50 g. mole)
in toluene (25 ml.) was added over 40 minutes, maintaining the
temperature of the mixture at 40-45C. The mixture was cooled to
20C. and concentrated hydrochloric acid (10.3 g. of a solution
prepared by adding 36 g. of HCl to 64 ml. of water, equivalent
20 to 3.7 g., 0.10 g. mole, of HCl) was added over 14 minutes main-
taining the temperature of the mixture at 15-20C.; the pH at the
end of the addition was 7-8. A mixture of an aqueous solution of
cyanamide (38.2 g. of a solution prepared by dissolving 50 g. of
cyanamide in 5Q ml. of water, equivalent to 19.1 g., 0.45 g. mole
of cyanamide) and concentrated hydrochloric acid (40.9 g. of
solution, equivalent to 14.7 g., 0.40 g. mole, of HC1) was then
added over 3 minutes; the pH at the end of this addition was 5-6.
1173~SO
Water (60 ml.) was added, the m.ixture was qtirred for 30 minutes
at 20-25C. and then the layers were separated. The aqueous
layer was extracted with toluene (2 x 50 ml.) and the toluene
solutions were combined, washed with saturated aqueous sodium
chloride solution (25 ml.) and evaporated to give dimethyl (N-
cyanoimido)carbonate (29.5 g., 51%) as a white solid.
-12-
