The Manufacture or Production of Pharmaceutical Compounds.
Year: 1895

page_text: Date of Application, 18th Sept., 1895
Complete Specification Left; 18th June, 1896-Accepted, 18th July, 1898
PROVISIONAL SPECIFICATION.
[Communicated from abroad by FARBENFABRIKEN, vormals FRIEDRICH
BAYER & Co.]
The Manufacture or Production of Pharmaceutical Compounds.
I HENRY EDWARD NEWTON of The Office for Patents, 6 Bream's Buildings,
Chancery Lane in the County of London, Patent Agent do..hereby declare. the
nature of this invention to be as follows:-
My foreign correspondents have found that the so-called phenoxylacetic acid
and its homologues and analogues such as have been described by W. Heintz (see
Poggendorf's Annalen vol. 109 page 489) by Fritsche (see Journal für Praktische
Chemie vol. 19 page 34 and vol. 20 page 267) and by Saarbach (see Journal für
Praktische Chemie vol. 21 page 151)-are capable of being. condensed with
phenolic bodies, a new series of aromatic compounds viz. phenoxylacetic phenyl
ether and its anologues, being thus produced. The researches of my foreign
correspondents have shewn that these new bodies are. of great value for certain
medical purposes.
In order to produce the above named compounds my foreign correspondents heat,
together with phenols, naphthols or substituted phenols, naphthols and the like,
alphyloxylacetic acids or alphyloxyl derivatives of other fatty acids, in the
presence of suitable condensing agents such as phosphorus trichloride or phosphorus..
oxychloride or phosphorus pentachloride or the like. My foreign correspondents.
hereinafter term radicles of aromatic hydrocarbons such as phenyl, tolyl, naphthyl.
and the like as "alphyls" This nomenclature is based on a proposition
of Bamberger (see Berichte der Deutschen chemischen Gesellschaft vol... 27,
page 2583). My foreign correspondents use for example in the process phenoxy!.
acetic acid, naphthoxylacetic acid, so called cresoxacetic acids (see German Letters
Patent 79514) alkylhydroxyphenox acetic acids and all the analogous derivatives.
which can for example readily be produced by the..interaction of equal molecular
proportions of an alkaline salt of a phenolic body and of monochloro acetic acid or
an analogous compound. For instance my foreign correspondents have prepared
in this manner:-from the sodium salt of meta cresol and mono chloro-acetic acid-
OCHCOOH
the shape of needles melting at from 102 and 103 degrees Centigrade.
From the sodium salt of para cresol and mono chloro acetic acid, para cresoxy!.
acetic acid, which crystallizes in the. form. of leaves melting at 154 degrees
Centigrade.
From the sodium salt of guaiacol and mono chloro acetic acid-ortho methoxy
phenoxyl acetic acid which crystallizes in the shape of needles melting at from
115 to 116 degrees Centigrade.
My foreign correspondents give-the following example in order to illustrate the
process in the production of the bereinbefore defined alpbyl oxyl acetic phenyl
hom the mouth being height

page_text: A mixture prepared from 20 parts of ortho methoxy phenoxyl acetic acid,
13.6 parts of guaiacol and 8.4 parts of phosphorus oxychloride is heated in a
vessel provided with a reflux condenser on an oil bath to about from 105 to 110
degrees Centigrade. Gaseous hydrochloric acid is evolved the reaction probably
taking place according to the following equation.-
When the reaction is finished the resulting mass is carefully washed with water
in order to remove the muriatic acid and the phosphoric acid formed in the process.
The residue thus obtained is recrystallized from alcohol.
The pure ortho methoxyphenoxyl acetic guaiacylether thus obtained crystallizes
in the form of small colourless needles melting at 80 degrees Centigrade. It is
insoluble in water but soluble with readiness in methyl alcohol, ethylalcohol,
acetone, benzene and the like, and it dissolves with difficulty in ligroine. It is
odourless and almost scentless.
Analogous compounds are produced by replacing the ortho methoxyphenoxyl
acetic used in the foregoing example by other alphyloxylacetic acids or by
alphy loxyl derivatives of other fatty acids derived from the homologues of the
acetic acid. Likewise other phenolic bodies may be used in the place of the
guaiacol used in the above example.
The process may also been carried out in acting on acid chlorides of alphyloxyl
acetic acids with alkaline salts of phenols or salts of alphyl oxylacetic acids may
be used instead of the free acids.
.
Such or other variations do not alter the nature of this invention which in
general relates to the production of alphyloxyl acetic alphyl ethers or of alphyl-
ethers of alphyloxyl derivatives of other fatty acids by the interaction of equal
molecular proportions of alphyloxylacetic acids or alphyloxyl derivatives or other
fatty acids and of phenols naphthols or substituted phenols, naphthols or the like.
Such alphyloxylacetic phenylethers are for example:-
Phenoxyl acetic phenylether C,H,O.CH,CO.OC,H,, crystallizing from ligroine
in the form of long prisms melting at from 59 to 60 degrees Centigrade.
Phenoxyl acetic guaiacylether C.H..O.CH,CO.OC,H,OCH,, crystallizing from
ligroine in the shape of white leaves melting at from 56 to 57 degrees Centigrade.
Orthocresoxylacetic orthocresylether crystallizing from watery alcohol in the
shape of long needles mélting at from 50 to 51 degrees Centigrade.
Orthocresoxylacetic guaiacylether crystallizing from ligroine in the form of
needles melting at from 81 to 82 degrees Centigrade.
Metacresoxyl acetic meta cresylether and meta cresoxylacetic guaiacylether
which have not been obtained in crystalline form.

page_text: Para cresoxylacetic guaiacylether crystallizing from ligroine in the shape of
prisms melting at from 82 to 83 degrees Centigrade.
Beta naphthoxylacetic meta cresylether crystallizing from ligroine in the shape
of small needles melting at from 91 to 92 degrees Centigrade.
Dated this 17th day of September 1895.
NEWTON & SON,
Agents for the Applicant.
The Manufacture or Production of Pharmaceutical Compounds.
I HENRY EDWARD NEWTON of The Office for Patents, 6 Bream's Buildings,
Chancery Lane in the County of London, Patent Agent, do hereby 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 statement :-
My foreign correspondents have found that the so-called phenoxy-acetic acid
and its homologues and analogues, such as have been described by W. Heintz
(see Poggendorf's Annalen, vol. 109, page 489) by Fritsche (see Journal für
Praktische Chemie, vol. 19, page 34, and vol. 20, page 267), and by Saarbach
(see Journal für Praktische Chemie, vol. 21, page 151, may be converted by
condensation with phenols into a new series of aromatic compounds, viz., phenoxy
acetic phenyl ether and its analogues. The researches of my foreign corre-
spondents have shown that these new compounds are of great value for certain
medical purposes.
In order to produce the above-named compounds, my foreign correspondents
heat mixtures of phenols or naphthols, or of substituted phenols or naphthols and
the like, with alphylaxy acetic acids, or alphyloxy-derivatives of other fatty
acids, to which suitable condensing agents, such as phosphorus trichloride, or
phosphorus oxychloride, or phosphorus pentachloride, or the like, have been added.
My foreign correspondents hereinafter apply the term "alphyl" to radicles of
aromatic hydrocarbons, such as phenyl, tolyl, naphthyl, and the like,-this
nomenclature being based on a proposition made by Bamberger (see Berichte der
Deutschen Chemischen Gesellschaft, vol. 27, page 2583). My foreign corre-
spondents use, for example, in the process, phenoxy acetic acid, naphthoxyacetic
acid, so-called cresoxy acetic acids (see German Letters Patent 79514), alkyl
bydroxy phenoxy acetic acids, and all the analogous derivatives which, for
example, can readily be produced by the interaction of molecular proportions of
an alkaline salt, of a phenolic compound, and mono-chloro acetic acid, or an
analogous compound. For instance, my foreign correspondents have prepared, in
this manner, from the sodium salt of meta cresol and monochloro acetic acid-
which crystallizes from water in needles melting at from 102 to 103 degrees
Centigrade; from the sodium salt of paracresol and monochloroacetic acid.
Paracresoxyacetic acid, which crystallizes in plates melting at 154 degrees
Centigrade; from the sodium salt of guaiacol and monochloroacetic acid.
Orthomethoxyphenoxyacetic acid, which crystallizes in needles melting at from
115 to 116 degrees Centigrade.
My foreign correspondents give the following example to illustrate the process
of producing the hereinbefore defined alphyloxyacetic phenyl ethers, the parts

page_text: A mixture of 20 parts of orthomethoxy phenoxyacetic acid, 13-6 parts of
guaiacoi, and 8.4 parts of phosphorus oxychloride, is heated in an oil bath, in a
vessel provided with a reflux condenser, at a temperature varying between about
105 and 110 degrees Centigrade. Hydrogen chloride is evolved, action probably
taking place in the manner represented by the following equation :—
6
When the action is at an end, the mass is carefully washed with water, in order
to remove the muriatic and phosphoric acids formed in the process. The residue
is recrystallized from alcohol.
The pure orthomethoxyphenoxy acetic guaiacylether thus obtained crystallises
in small colorless needles melting at 80 degrees Centigrade. It is insoluble in
water, but readily soluble in methyl alcohol, ethylalcohol, acetone, benzene, and
the like, but it dissolves with difficulty in ligroin. It is odorless and alin st
tasteless.
Analogous compounds are produced by substituting, for the orthomethoxy-
phenoxyacetic acid used in the foregoing example, other alphyloxyacetic acids, or
alphyoxy derivatives of other fatty acids derived from the homologues of acetic
acid. Other phenolic compounds may also be used instead of the guaiacol prescribed
in the above example.
The process may also be carried out by acting on acid chlorides of alphyloxy
acetic acids with alkaline salts of phenols, or salts of alphyl oxyacetic acids may
be used instead of the acids.
Such or other variations do not alter the nature of this invention, which,
speaking generally, relates to the production of alphyloxyacetic alphyl ethers, or
of alphyl ethers of alphyloxy derivatives of other fatty acids, by the interaction of
molecular proportions of alphyloxy acetic acids, or alphyloxy derivatives of
other fatty acids, and of phenols, uaphthols, or substituted phenols, naphthols,
or the like.
Such alphyloxy acetic phenyl ethers are, for example :-
Phenoxyacetic phenylether C,H,OCH,CO.OCHы, crystallising from ligroin
in long prisms melting at from 59 to 60 degrees Centigrade.
Phenoxy acetic guaiacylether C.H.O.CH,CO.OC¸HOCH,, crystallizing from
ligroin in white plates melting at from 56 to 57 degrees Centigrade.
Orthocresoxyacetic ortho cresylether, crystallizing from aqueous alcohol in long
needles melting at from 50 to 51 degrees Centigrade.
Orthocresoxyacetic guaiacylether, crystallizing from ligroin in needles melting
at from 81 to 82 degrees Centigrade.
Metacresoxy acetic metacresylether and metacresoxy acetic guaiacylether, which
have not been obtained in a crystalline form.

page_text: Paracresoxy acetic guaiacylether, crystallizing from ligroin in prisms melting at
from 82 to 83 degrees Centigrade.
Betanaphthoxy acetic metacresylether, crystallizing from ligroin in small needles.
melting at from 91 to 92 degrees Centigrade.
Having now particularly described and ascertained the nature of this inven-
tion and in what manner the same is to be performed, as communicated to me.
from abroad, I declare that what I claim is :-
1. The production of phenoxy-acetic phenylether, and of its homologues and
analogues, from phenoxyacetic acid and its homologues and analogues respectively,.
and phenolic compounds.
2. The process of producing phenoxy acetic phenylether and its homologues.
and analogues, which process consist in heating phenoxy acetic acid, or its
homologues and analogues, together with phenols, naphthols, or substituted
phenols, naphthols, or the like, in the presence of condensing agents, such as
phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or
the like.
3. In the process defined in the foregoing second claim, on the one hand, the
use of phenoxy acetic acid, orthomethoxy phenoxy acetic acid, orthocresoxy acetic
acid, metacresoxyacetic acid, paracresoxyacetic acid, naphthoxyacetic acids, and
analogous or homologous compounds; on the other hand, the use of phenol, of
alpha or beta naphthol, of cresols, of guaiacol, and the like phenolic compounds.
4. The use of the herein before defined alphyloxy acetic alphylethers for medicinal
purposes.
5. As new articles of manufacture, the compounds produced by the process.
herein described.
Dated this 18th day of June 1896.
NEWTON & SON,
Agents for the Applicant..