Production of Oxyphenyl-guanidines and their Derivatives.
Year: 1897

page_text: Date of Application, 20th Oct, 1897
Complete Specification Left, 13th July, 1898-Accepted, 17th Sept., 1898
PROVISIONAL SPECIFICATION.
Production of Oxyphenyl-guanidines and their Derivatives.
A communication from abroad by CHEMISCHE FABRIK VON HEYDEN, GESELLSCHaft
mit BESCHRANKTER HAFTUNG, of Radebeul, near Dresden, Saxony, German
Empire, Manufacturers.
I, JOHN CLAYTON MEWBURN, of the Firm of J. C. Mewburn and Ellis, of 55 and
56, Chancery Lane, in the County of London, Chartered Patent Agents, do hereby
declare the nature of this invention to be as follows:-
This invention consists in the manufacture of the hitherto unknown guanidines of
This new class of substances produced by my foreign correspondents is of special
industrial importance by reason of its capability of being employed as an
anæsthetic.
Not all oxyphenyl-guanidines, but only those, of the above formula, characterized
especially by the middle group (=NCHOR¹), constituting a hitherto unknown
class of substances possess this industrial value. The substances of this new class of
bodies possess also a germicidal action in addition to their anæsthetic action.
In the following example there is particularly described the manufacture of para-
triethoxy-phenyl-guanidine.

page_text: There also remains a certain residual amount of diethoxydiphenyl-thio-urea
CS(NHCHOC,H), which is either contained originally in the primary substance
or is formed as a bye product of the decomposition. The substance, which is readily
decomposable and which is produced by mixing sulphide of carbon and para-
phenetidine, is therefore probably the salt
(NHCH₂OC₂H)2 + 2PbS + 2H₂O
NCH OC₂H.
The reaction may be carried out in the following manner :-
Any one of the products of reaction resulting, from carbon disulphide and para-
phenetidine, is mixed in hot alcohol with one equivalent of para-phenetidine, and is
then desulphurized with an excess of lead oxide or other desulphurizing agent, until
a filtered sample produces no longer any blackening with an addition of lead oxide.
Separation is effected by filtering hot from the lead sulphide, and the alcohol is
evaporated. The oily residue is dissolved in hot dilute hydrochloric acid. This
solution is treated, when necessary, with animal charcoal, and after filtration and
cooling, colorless coarse needle crystals are separated out. These consist of hydro-
chlorate of triparaethoxyphenyl-guanidine having a melting point of 197°.
The substance when dried in the "exsiccator" has yielded the following values :-
:-

page_text: On being heated to 1100 the glassy crystalline salt assumes an efflorescent aspect.
On mixing an aqueous solution of the same with alkali, flakes are precipitated which
when slightly heated melt together to form a colorless oil which dissolves in hydro-
chloric acid with regeneration of the chlorine-hydrate, but is extremely difficultly
soluble in water, whilst it is readily soluble in alcohol, ether and benzol. The
separated oil sets in cooling, and in this form has a melting point of about 55°.
Attempts at acetylization with CH, COCI were not successful.
d. If, instead of para-phenetidine, there are employed the homologues,
produced from p-apisidine has a melting point of 201°C.
From
OC₂H 1
CH, CH, 2
NH,
4
there is obtained the guanidine C
(NHC,HOC,H)2
NCH OCH HCI
e. If in the process of production described under c there is used thio-carbaminate
salt or thio-ureas, founded on aromatic bases, which are different from the amido-
phenol body added in the desulphurization, then mixed guanidines are obtained. If,
for instance, in the example described under c, instead of phenetidine, the p-anisidine
be employed there is produced the mixed guanidine

page_text: an oil whose hydrochlorate salt is soluble in water, but appears to be difficult to
crystallize.
f. Instead of lead oxide, any other desired desulphurizing agents may be employed,
for instance, other metallic oxides or hydrated oxides, also metallic chlorides, such as
for instance HCl, or the compounds of HCl, and phenetidine
or of similar constitution)
Also metallic powders (copper, aluminium &c.); further, iodine and nitrous acid
may, as is well known, be used as agents for destroying sulphuretted hydrogen in the
manufacture of guanidine.
g. Alcohol may be replaced by other neutral solvents, or a solvent may be wholly
dispensed with. In the latter case there is preferably employed as a desulphurizing
agent, a metallic powder, for example copper powder, and the mixture therewith is
heated with thio-urea, with the omission of the addition of the base. Therefore in
the manufacture of triphenetol-guanidine without a solvent, the addition of
amido-phenetol is omitted and the diphenetol-thio-urea is simply melted with
the metal powder, for example, reduced copper, and the melt is boiled with dilute
hydrochloric acid. The solution, when cold, yields the crystals, already described
under c of hydrochlorate of triphenetol-guanidine. Even the addition of the metallic
powder may be omitted, because the great supply of heat acts of itself as a desul-
phurizing agent. For instance it is sufficient to heat the diphenetol-thio-urea by
itself to about 150° to 200°.
h. Instead of thio-urea, the corresponding urea can be also employed. Then a
dehydration takes place instead of a removal of sulphuretted hydrogen. For example,
on heating 5 parts of diphenetol-urea with 2.3 parts of phenetidine and 1 part of
phosphorus-trichloride, penta-chloride, or oxychloride, or with the corresponding
quantity of phosphorus-trioxide or pentaoxide, or meta-phosphoric acid, to about 170°,
and if the melt when cold is dissolved in hot dilute hydrochloric acid, the hydro-
chlorate of triphenetol-guanidine crystallizes out of the solution.
Instead of using any dehydrating chlorides or anhydrides caustic alkalies or alkali-
alcoholates may be used. If for example, 5 parts of diphenetol-urea be heated with
1 part of powdered sodium-hydro-oxide or sodium-methylate, or without any addition,
to melting point for some time, and the cooled melt is dissolved in hot dilute hydro-
chloric acid, then when the solution is cold, the hydrochlorate of tri-phenetol-guani-
dine cystallizes out.
i. All the herein before described variations in the mode of manufacture are based
obviously on the intermediate formation of carbo-di-imides. The process does not
take place as specified under c in one phase, or stage, but in two stages :-
The reactions may be effected in these separate stages, but then in desulphuriza-
tion, a solvent must be used which is neutral to the extremely reactive carbo-di-imide,
such as for instance, benzol.
For example, diphenetol-thio-urea is dissolved in benzol, and this solution is heated
with lead oxide until the desulphurization is completed, filtered, and gaseous hydro-
chloric acid is passed into the filtrate. The hydrochlorate of carbo-diphenetol-di-
imide then separates out in the form of white crystals. These melt at 190-200°,

page_text: with decomposition, and form with alcohol or water, especially in the presence of
alkalies very rapidly whilst taking up are molecule of HO, the corresponding
uroo
C
=
(NCHOC₂H)2 + H₂O = 00 =
(NHCH₂OC₂H)2.
But the carbo-di-imide combines with bases to form guanidine and with p-phene
tidine to form triphenetol-guanidine, as specified by the above stated stage No. 2.
In the substitution of thio-urea by the corresponding urea, as stated under h water is
split off in the first stage, and carbo-di-imide is also formed from the urea, which
carbo-di-imide combines in the second stage with the added phenetidine or with the
phenetidine produced by the action of the alkali upon another portion of the urea, to
form guanidine.
All the herein before described variations are thus really only more or less compli-
cated modes of carrying out the theoretically most simple mode of production, viz.:—
the simple melting or dissolving together of a carbo-di-imide with an amido-phenol
body.
In effecting the reaction in the said two stages, simple as well as mixed guanidines
can be produced. As an example of simple guanidines. The production of
triphenetol-guanidine by simply bringing together C = (NCHОCH), and amido-
phenetol.
As an example of mixed guanidines. The production of phenetol-di-anisol-guanidine
by bringing together C (NCH,OCH,), and amido-phenetol
The following guanidines can be produced in accordance with this invention :-

page_text: Production of Oxyphenyl-guanidines and their Derivatives.
A communication from abroad by CHFMISCHE FABRIK VON HEYDEN, GESELLSCHAFT
mit BESCHRANKTER HAFTUNG, of Radebeul, near Dresden, Saxony, German
Empire, Manufacturers.
I, JOHN CLAYTON MEWBURN, of the Firm of J. C. Mewburn and Ellis, of 55 and 56
Chancery Lane, in the County of London, Chartered Patent Agents, do hereby 1
declare the nature of this invention, and in what manner the same is to be
performed, to be particularly described and ascertained in and by the following
tatement :-
This invention consists in the manufacture of the hitherto unknown guanidines

page_text: aromatic compound, and R¹ represents hydrogen or alkyl or alkylene, characterised
by the application of the known methods of preparing guanidine to the compounds
and their nomologues.
This new class of substances produced by my foreign correspondents is of special
industrial importance by reason of its capability of being employed as anaesthetics.
These substances possess a powerful anesthetic action even in the state of a highly
dilute
aqueous solution.
Not all oxyphenyl-guanidines, but only those of the above formula, characterised
especially by the middle group (=NCHOR¹), conuing a hitherto unknown
class of substances possess this industrial value. The substances of this new el iss of
bodies possess also a germicidal action in addition to their aesthetic action.
In the following example there is particularly described the manufacture of para-
triethoxy-phenyl-guanidine.
a/. Sulphide of carbon and para-amido-phenetol are mixed together approximately
in the proportion of 1:2. The latter substance may be previously diluted with
about the same or double the volume of alcohol or ether. The mixture sets quickly
with the precipitation of a solid whitish yellow substance which after being washed.
in ether, melts at about 70° C. This substance may be redecomposed back into
sulphide of carbon and amido-phenetol, by boiling with water or treating with acid.
There also remains a certain residual amount of diethoxydiphenyl-thio-urea
CS(NHC.H₂OC₂H,), which is either contained originally in the primary substance
or is formed as a bye product of the decomposition. The substance which is
readily decomposable and which is produced by mixing sulphide of carbon and para-
phenetidine, is therefore probably the salt
CS(NHCHOCH¸), + NH₂CHОСH + Pb = C
NOOIT

page_text: The reactions may be carried out in the following manner :-
Any one of the products of reaction resulting from carbon disulphide and para-
phenetidine, is mixed in hot alcohol with ore equivalent of para-phenetidine, and is
then desulphurized with an excess of lead oxide or other desulphurizing agent, until
a filtered sample produces no longer any blackening with an addition of lead oxide.
Separation is effected by filtering hot from the lead sulphide, and the alcohol is
evaporated. The oily residue is dissolved in hot dilute hydrochloric acid. This
solution is treated, when necessary, with animal charcoal, and after filtration and
cooling, colorless coarse needle crystals are separated out. These consist of
hydrochlorate of tripara-ethoxyphenyl-guanidine having a melting point of 197°.
The air-dried substance has yielded the following values.
On being heated to 110° the glassy crystalline salt assumes an efflorescent aspect.
On mixing an aqueous solution of the same with alkali, flakes are precipitated which
when slightly heated melt together to form a colorless oil which dissolves in
hydrochloric acid with regeneration of the hydrochlorate, but is extremely difficultly
soluble in water, whilst it is readily soluble in alcohol, ether and benzol.
separated oil sets in cooling, and in this form has a melting point of about 55º.
Attempts at acetylization with CH,COCl were not successful.
The
d/. If, instead of para-phenetidine, there are employed the homologues

page_text: el. If in the process of production described under c there is used thio-carbaminate
salt or thio-ureas, founded on aromatic bases, which are different from the amido-
phenol body added in the desulphurization, then mixed guanidines are obtained. If,
for instance, in the example described under c, instead of phenetidine, the p-anisidine
be employed there is produced the mixed guanidine-
H
f. Instead of lead oxide, any other desired desulphurizing agents may be employed,
for instance, other metallic oxides ar hydrated oxides also metallic chlorides, such as
for instance HgCl₂, or the compounds of HgCl₂ and phenetidine (Cl-Hg-N HOCH
'Ca
[probable formula] or of similar constitution).
Also metallic powders (copper, aluminium, &c.) furthur, iodine and nitrous acid
may, as is well known, be used as agents for destroying sulphuretted hydrogen in the
manufacture of guanidine.
g/. Alcohol may be replaced by other neutral solvents, or a solvent may be wholly
dispensed with. In the latter case there is preferably employed as a desulphurizing
agent a metallic powder, for example, copper powder, and the mixture therewith is
heated with thio-urea, with the omission of the addition of the base. Therefore in
the manufacture of triphenetol-guanidine without a solvent, the addition of amido-
phenetol is omitted and the diphenetol-thio-urea is simply melted with the metal
powder, for example, reduced copper, and the melt is boiled with dilute hydrochloric
acid. The solution, when cold, yields the crystals, already described under c of
hydrochlorate of triphenetol-guanidine. Even the addition of the metallic powder

page_text: may be omitted, because the great supply of heat acts of itself as a desulphurizing
agent. For instance it is sufficient to heat the diphenetol-thio-urea by itself to
about 150° to 200°.
h. Instead of thio-urea, the corresponding urea can be also employed. Then a
dehydration takes place instead of a removal of sulphuretted hydrogen. For example,
on heating 5 parts of diphenetol-urea with 23 parts of phenetidine and 1 part of
phosphorus-trichloride, penta-chloride, or oxy-chloride, or with the corresponding
quantity of phosphorus-trioxide and pentaoxide, or meta-phosphoric acid, to about
170°, and if the melt when cold is dissolved in hot dilute hydrochloric acid, the
hydrochlorate of triphenetol-guanidine crystallizes out of the solution.
Instead of using any dehydrating chlorides or anhydrides caustic alkalies or alkali-
alcoholates may be used. If for example, 5 parts of diphenetol-urea be heated with
I part of powdered sodium-hydro-oxide or sodium-methylate, or without any addi-
tion; to melting point for some time, and the cooled melt is dissolved in hot dilutė
hydrochloric acid, then when the solution is cold, the hydrochlorate of tri-phenetol-
guanidine crystallizes out.
/. All the herein before described variations in the mode of manufacture are based
obviously on the intermediate formation of carbo-di-imides. The process does not
take place as specified under c iu one phase, or stage, but in two stages:
C = (NC¸HOC„H¸), + H₂O = CO=(NHCH¿OC₂HË)²
But the carbo-di-imide combines with bases to form guanidine and with p-phene-
tidine to form triphenetol-guanidine as specified by the above stated stage No. 2.
In the substitution of thio-urea by the corresponding urea, as stated under h water
is split off in the first stage, and carbo-di-imide is also formed from the urea, which
carbo-di-imide combines in the second stage with the added phenetidine or with the
phenetidine produced by the action of the alkali upon another portion of the urea, to
form guanidine.
All the herein before described variations are thus really only more or less compli-
cated modes of carrving out the theoretically most simple mode of production, viz. :-
the simple melting or dissolving together of a carbo-di-imide with an amid -phenol
body.
In effecting the reaction in the said two stages, simple as well as mixed guanidines
can be produced.
As an example of simple guanidines -The production of tri-phenetol-guanidine by
simply bringing together C=(NC,HOC₂H,), and amido phenol.

page_text: As an example of mixed guanidines:-The production of phenetol-di-anisol-
guanidine by bringing together C-(NC,H,OCH,), and amido-phenetol.
The following guanidines can be produced in accordance with this invention :-

page_text: Having now particularly described and ascertained the nature of the said inven-
tion as communicated to me, and in what manner the same is to be performed,
declare that what I claim is.
1. The process for the production of simple and mixed oxyphenyl-guanidines of
των
1. The process for the production of simple and mixed oxyphenyl-guanidines of
the formula
NHR
CNCHOR¹
NHR
(in which R and R1 represent hydrogen or the monovalent residue of a fatty or
aromatic compound, and R¹ hydrogen or alkyl or alkylene) which process consists in
causing a carbo-di-imide (it being immaterial whether the carbo-di-imide is produced
in an intermediary manner, or whether it exists originally in its complete form) to
react with an amido-phenol of the constitution NH,CHOR¹, in which R¹ may
represent hydrogen, alkyl, and alkylene.
2. The particular method of carrying out the process specified in Claim 1, which
method consists in treating the reaction products from carbon bisulphide and amido-
phenol bodies (such as thio-carbaminate salts, thio-ureas and the like; with
desulphurizing agents in the presence of amido-phenol bodies, substantially as
described.
3. The particular method of carrying out the process specified in Claim 1 which
method consists in treating the reaction products referred to in Claim 2, with desul-
phurizing agents without separate addition of amido-phenol bodies, substantially as
described.
4. The particular method of carrying out the process specified in Claim 1 which
method consists in heating the reaction products referred to in Claim 2 to a temperature
of from 150° to 200° C., substantially as described.
5. The particular method of carrying out the general process specified in Claim 1,
which method consists in treating ureas corresponding to the thio-ureas referred to in
Claim 2 with dehydrating agents including caustic alkalies and alkali-alcoholates,
substantially as described.
6. As new products the following guanidines being members of the new class
herein before referred to and capable of being produced as herein before described :-
=