Manufacture of Amidoacylamidocarboxylic Acid Esters.
Year: 1898

page_text: Date of Application, 20th Oct., 1898
Complete Specification Left, 7th July, 1899-Accepted, 19th Aug., 1899
PROVISIONAL SPECIFICATION.
Manufacture of Amidoacylamidocarboxylic Acid Esters.
I, OLIVER IMRAY, of Birkbeck Bank Chambers, Southampton Buildings, Chancery
Lane, in the County of London, Chartered Patent Agent, do hereby declare the
nature of this invention (as communicated to me from abroad by The Farbwerke
vormals: Meister Lucius and Brüning, of Hoechst a/Main, in the Empire of
Germany, Chemical Manufacturers,) to be as follows:-
By the action of aliphatic halogen-substituted acid chlorides, such, for instance, as
chloracetylchloride, upon amidocarbonic acid esters of the aromatic series are obtained
derivatives of halogen-acylamides, that is to say, the radicle of the halogen-substituted
acid enters the amidogroup.
If primary or secondary amines are allowed to act upon these halogenacylamido-
derivatives of amido carbonic acid esters, then new compounds are obtained, namely,
glycocoll derivatives of amidocarbonic acid esters.
The same glycocoll derivatives of amidocarbonic acid esters may also be obtained
by treating halogenacylamido-derivatives, produced by the action of halogen-
substituted acid chlorides upon amidocarbonic acids, with primary or secondary
amines and by finally etherifying the glycocoll derivatives of amidocarbonic acids thus
resulting.
The glycocoll derivatives of amidocarbonic acid esters, obtained in this way, are
basic compounds, characterized by their anæsthetic property.
My foreign correspondents obtain such glycocoll derivatives, for instance, from
ortho-, meta-, para-amidobenzoic acid, ortho., para-amido salicylic acid, para-amido-
meta-oxybenzoic acid, meta-amido-para-oxybenzoic acid, amido-cinnamic acid, as
illustrated by the following examples.
To a solution of 12 parts by weight of the methyl ester of anthranilic acid in
100 parts by weight of benzene are added 10 parts by weight of chloracetylchloride
and the mixture is heated on the water bath till the evolution of hydrochloric acid
ceases, which takes place after about 2 hours. Then about two thirds of the benzene.
are distilled off and the residue is allowed to cool, when the methyl ester of chlor-
acetylanthranilic acid separates; it crystallizes from absolute alcohol in fine white
needles having a melting point 92° C.
To 4.1 part by weight of a 32 % aqueous solution of methylamine, diluted with
alcohol, is added, while shaking, an alcoholic solution of 5 parts by weight of the
methyl ester of chloracetylanthranilic acid, the whole being heated in a vessel provided
with an inverted condenser or preferably in a closed vessel for about 2 hours on the
water bath, then the alcohol is distilled off, the residue is acidified with dilute aqueons
[Price 8d1

page_text: hydrochloric acid, filtered, if necessary, from the insoluble substance and the filtrate,
after an excess of potassium carbonate has been added, is extracted with ether. On
evaporation there remains the methyl ester of methylglycocollanthranilic acid as a
basic oil, which forms together with alcoholic hydrochloric acid a hydrochloride,
obtained from alcohol and ether in fine crystals melting, while decomposing at 202°º C.
and yielding with nitrous acid a nitro-compound.
34 parts by weight of methyl para-amidosalicylate are dissolved in 220 parts by
weight of benzene and heated with 24 parts by weight of chloracetylchloride until
there is no further escape of hydrochloric acid. The methyl ester of chloracetyl-p-
amidosalicylic acid partly separates during the reaction and completely on cooling, as
a pale violet coloured crystallinė mass; it is filtered and washed with benzene. This
compound crystallizes from absolute alcohol in longish laminae having the melting
point 158° C.
45 parts by weight of the methyl ester of chloracetyl-p-amido salicylic acid and
28 parts by weight of diethylamine are heated in 100 parts by weight of alcohol for
2 hours in a vessel provided with an inverted condenser; the alcohol is then
evaporated, the residue is treated with a dilute solution of soda and extracted with
ether.
On distilling off the solvent, there remains the methyl ester of diethylglycocoll-p-
amido salicylic acid as an oil; its hydrochloride crystallizes from absolute alcohol in
prisins having the melting point 185° C. It yields in an aqueous solution with
ferric chloride a product of reaction of violet colour.
EXAMPLE III.
30 grammes of para-amidosalicylic acid are heated with 300 cubic centimetres of:
benzene and 24 grammes of chloracetylchloride on the water bath provided with an
inverted condenser for so long as hydrochloric acid escapes. When cooled, it is
filtered and the remaining mixture of chloracetylamidosalicylic acid and hydrochloride
of amidosalicylic acid is diluted with water to remove the acid. Then the chlor-
acetylamidosalicylic acid is crystallized from dilute alcohol; it forms needles, melting a
at 237° C.
22.5 grammes of chloracetyl-p-amidosalicylic acid are heated with 14.6 grammes
of diethylamine and 60 cubic centimetres of alcohol for 2 hours in a vessel provided
with an inverted condenser.
bath.
Then the alcohol is distilled off and to the residue are added 110 cubic centimetres 3
of a 10 per cent. soda solution and the diethylamine is evaporated on the water
After adding 20 grammes of concentrated hydrochloric acid of 35 per cent.,
the whole is concentrated by evaporation and by adding sodium acetate the diethyl-
amidoacetylamidosalicylic acid is precipitated. It crystallises from water and
decomposes at 250° C. In order to etherify it, methyl alcohol is poured on the acid 4
while hydrochloric acid is introduced; the hydrochloride of the acid first resulting
dissolves slowly.
From this solution, after diluting with water and adding a soda solution, the ester
thus formed may be separated by shaking with ether. From the ethereal solution
dried with potash, the hydrochloride of the ester is separated by introducing 4
bydrochloric acid gas.
Dated this 20th day of October 1808
ABEL & IMRAY,
Agents for the Applicant.

page_text: Manufacture of Amidoacylamidocarboxylic Acid Esters.
I, OLIVER IMRAY, of Birkbeck Bank Chambers, Southampton Buildings, Chancery
Lane, in the County of London, Chartered Patent Agent, do hereby declare the
nature of this invention (as communicated to me from abroad by The Farbwerke
vormals: Meister Lucius & Brüning, of Hoechst a/Main, in the Empire of Germany,
Chemical Manufacturers,) and in what manner the same is to be performed to
be particularly described and ascertained in and by the following statement:-
By the action of aliphatic halogen-substituted acid chlorides, such, for instance, as
chloracetylchloride, upon amidocarboxylic acid esters of the aromatic series are
obtained derivatives of halogen-acylamides, that is to say, the radicle of the halogen-
substituted acid enters the amidogroup.
If primary or secondary amines are allowed to act upon these halogenacyl-
amido-derivatives of amidocarboxylic acid esters, then new compounds are obtained,
namely, glycocoll derivatives of amidocarboxylic acid esters.
The same glycocoll derivatives of amidocarboxyl acid esters may also be obtained
by treating halogenacylamido-derivatives, produced by the action of halogen-substi-
tuted acid chlorides upon amidocarboxylic acids, with primary or secondary amines and
by finally etherifying the glycocoll derivatives of amidocarboxylic acids thus resulting.
The glycocoll derivatives of amidocarboxylic acid esters, obtained in this way are
basic compounds, characterized by their anaesthetic property.
My foreign correspondents obtain such glycocoll derivatives, for instance, from
ortho-, meta-, and para-amido-benzoic acid, ortho- and para-amido salicylic acid, para-
amido-meta-oxybenzoic acid, meta- amido-para-oxybenzoic acid, and amido-cinnamic
acid, as illustrated by the following examples.
EXAMPLE I.
To a solution of 12 parts by weight of the methyl ester of anthranilic acid in 100
parts by weight of benzene are added ten parts by weight of chloracetyl-chloride and
the mixture is heated on the water bath till the evolution of hydrochloric acid ceases,
which takes place after about 2 hours. Then about two thirds of the benzene are
distilled off and the residue is allowed to cool, when the methyl ester of chloracetyl-
anthranilic acid separates; it crystallizes from absolute alcohol in fine white needles
having a melting point 92° C.
To 4.1 parts by weight of a 32 per cent. aqueous solution of methylamine, diluted
with alcohol, is added, while shaking, an alcoholic solution of 5 parts by weight of
the methyl ester of chloracetylanthranilic acid, the whole being heated in a vessel
provided with an inverted condenser, or preferably in a closed vessel, for about 2 hours
on the water bath, then the alcohol is distilled off, the residue is acidified with dilute
aqueous hydrochloric acid, filtered, if necessary, from the insoluble substance and the
filtrate, after an excess of potassium carbonate has been added, is extracted with
ether. On evaporation there remains the methyl ester of methylglycocollanthranilic
acid as a basic oil, which forms together with alcoholic hydrochloric acid a bydro-
chloride, obtained from alcohol and ether in fine crystals melting, while decomposing,
at 202° C. and yielding with nitrous acid a nitroso-compound.
MAAMI LE
34 parts by weight of methyl para-amidosalicylate are dissolved in 220 parts by
weight of benzene and heated with 24 parts by weight of chloracetylchloride until
there is no further escape of hydrochloric acid. The methyl ester of chloracetyl-p-

page_text: as
it
a pale violet coloured crystalline mass; 15 filtered and washed
benzene.
with
This compound crystallizes from absolute alcohol in longish laminae having the
melting point 158° C.
45 parts by weight of the methyl ester of chloracetyl-p-amido-salicylic acid and 28
parts by weight of diethylamine are heated in 100 parts by weight of alcohol
for 2 hours in a vessel provided with an inverted condenser; the alcohol is then
evaporated, the residue is treated with a dilute solution of soda and extracted
with ether.
On distilling off the solvent, there remains the methyl ester of diethylglycocoll-p-
amidosalicylic acid as an oil; its hydrochloride crystallizes from absolute alcohol in
prisms having the melting point 185° C. It yields in an aqueous solution with ferric
chloride a product of reaction of violet colour.
EXAMPLE III.
30 grammes of para-amidosalicylic acid are heated with 300 cubic centimetres of
benzene and 24 grammes of chloracetylchloride on the water bath in a vessel provided
with an inverted condenser for so long as hydro-chloric acid escapes.
When cooled,
it is filtered and the remaining mixture of chloracetylamidosalicylic acid and hydro-
chloride of amidosalicylic acid is diluted with water to remove the acid. Then the
chloracetylamidosalicylic acid is crystallized from dilute alcohol; it forms needles,
melting at 237° C.
22.5 grammes of chloracetyl-p-amidosalicylic acid are heated with 14.6 grammes
of diethylamine and 60 cubic centimetres of alcohol for 2 hours in a vessel provided
with an inverted condenser.
Then the alcohol is distilled off and to the residue are added 110 cubic centimetres
of a 10 per cent. soda solution and the diethylamine is evaporated on the water bath.
After adding 20 grammes of concentrated hydrochloric acid of 35 per cent. strength,
the whole is concentrated by evaporation and by adding sodium acetate the diethyl-
amidoacetylamidosalicylic acid is precipitated. It crystallises from water and
decomposes at 250° C.
In order to etherify it, methylalcohol is poured on the acid while hydrochloric
acid is introduced; the hydrochloride of the acid first resulting dissolves
slowly.
From this solution, after diluting with water and adding a soda solution, the ester
thus formed may be separated by shaking with ether. From the ethereal solution
dried with potash, the hydrochloride of the ester is separted by introducing hydro-
chloric acid gas.
By the same method the following further glycocollamidocarboxylic acid esters are
obtained (the melting points are given in degrees Centigrade).
HCl-ethylglycocoll-p-amidobenzoic acid ethylester, cryst., M.P. 225°; free
base, needles M.P. 105°-106° C.
HCl-ethylglycocollanthranilic acid methylester, white cryst., M.P. 191°; free
base, oil.
HBr-dimethylglycocollanthranilic acid methylester, white cryst., M.P. 195°;
free base, oil.
HBr-diethylglycocollanthranilic acid methylester, needles, M.P. 120°; free
base, oil.
HCl-methylglycocoll-m-amidobenzoic acid methylester, white cryst., M.P. 200°;
free base, solid, M.P. 59°-60° C.
HCl-diethylglycocoll-m-amidobenzoic acid methylester, white cryst., M.P. 180°;
free base, oil.
HCl-methylglycocoll-p-amidobenzoic acid methylester, white cryst., M.P. 2130
free base, solid, M.P. 96°-98° C.

page_text: HBr-diethylglycocoll-p-amidobenzoic acid methylester, granular cryst., M.P.
172°; free base, M.P. 60°.
HI-dimethylglycocoll-p-amidobenzoic acid ethylester, laminae, M.P. 85°; free
base, oil.
HCl-diethylglycocoll-o-amidosalicylic acid methylester, needles, M.P. 80°-82°;
free base, solid, M.P. 40°-42°.
HCl-ethylglycocoll-p-amidosalicylic acid methylester, white cryst., M.P. 230°;
free base, solid, M.P. 60°.
HCl-dimethylglycocoll-p-amidosalicyclic acid methylester, needles, M.P. 237°;
free base, solid, M.P. 59°-60°.
HCI-diethylglycocoll-p-amidosalicylic
198.5° free base, oil.
acid ethylester, white cryst., M.P.
HCI-diethyglycocoll-p-amido-m-oxybenzoic acid methylester, needles, M.P. 99°;
free base, solid, M.P. 158°.
HCI-diethylglycocoll-p-amidocinnamic
1980-199° free base, viscous oil.
acid methylester, needles, M.P.
HCl-diethylglycocoll-m-amidocinnamic acid methylester, needles, M.P. 165°;
free base, thick oil.
HCl-diethylglycocoll-m-amido-p-oxybenzoic acid methylester, white cryst.,
laminae M.P. 175°.
Having now particularly described and ascertained the nature of this inven-
on and in what manner the same is to be performed I declare that what I
ain is:-
1. The herein described manufacture of glycocoll derivatives of the esters of
omatic amido- and amido-oxycarboxylic acid esters, by allowing primary or
condary bases to act upon the chloracyl derivatives of the said esters.
2. The herein described manufacture of alkylglycocoll derivatives of the esters of
omatic amido- and amido-oxycarboxylic acids by treating the halogen-acylamido-
erivatives, obtained by the action of halogen-substituted acid chlorides upon
omatic amido- and amido-oxycarboxylic acids, with primary or secondary amines
d esterifying the resulting alkylglycocoll-amidocarboxyl acids or -amido-oxycarboxylic
ids.
3. The alkylglycocoll derivatives of aromatic amido- and amido-oxycarboxylic acid
ters, manufactured as above set forth in Nos. 1 and 2.
Dated this 7th day of Tul, 1800