Improvements in the Production of a Pharmaceutical Compound.
Year: 1896

page_text: Date of Application, 5th Nov, 1896
Complete Specification Loft 28th July 1807 Accented 25th Sant 1907
Complete Specification Loft, 28th July, 1207 Accented, 25th Sept 1907
PROVISIONAL SPECIFICATION.
[Communicated from abroad by THE FARBENFABRIKEN VORMALS FRIEDRICH
BAYER & Co., of Elberfeld Germany.]
Improvements in the Production of a Pharmaceutical Compound.
I, HENRY EDWARD NEWTON of the Office for Patents, 6 Breams Buildings,
Chancery Lane in the County of London, Patent Agent, do hereby declare the
nature of this invention to be as follows:-
Codeine has been produced hitherto by methylating morphine by means of a
mixture of methyl-iodide and sodium alcoholate, or by means of methyl-sulphuric
alkali. These methods, however, do not yield good results, considerable quantities
of morphine remaining unaltered.
My foreign correspondents have now found that the methylation of morphine
is readily effected by treating the latter with diazomethane (see Berichte der
Deutschen Chemischen Gesellschaft, Vol. 27, page 1888, and Vol. 28, pages 855
and 1624), an almost quantitative yield of codeine being thus obtained.
following example will illustrate the production of codeine by means of the new
process hereinbefore referred to.
EXAMPLE.
The
Into a cooled solution, in ether, of one molecular proportion of diazo methane
(which compound can be determined by means of iodine solution), one molecular
proportion of morphine, either in a finely powdered state, or in an absolute
methylic or ethylic alcoholic solution, is introduced. A development of azote
takes place, the solution being discolored. By evaporating the solvent, codeine
is produced, which is purified in the usual manner.
Dated this 5th day of November 1896
Improvements in the Production of a Pharmaceutical Compound.
I HENRY EDWARD NEWTON of the Office for Patents, 6 Breams 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:-
Codeine has been produced hitherto by methylating morphine by means of a
mixture of methyl-iodide and sodium alcoholate, or by means of methyl sulphuric

page_text: alkali. These methods, however, do not yield good results, considerable quantities
of morphine remaining unchanged.
My foreign correspondents have now. found that the methylation of morphine
is readily effected by treating the latter with diazomethane (see Berichte der
Deutschen Chemischen Gesellschaft, Vol. 27, page 1888, and Vol. 28, pages 855
and 1624), in or without the presence of alkalies. The following examples will
illustrate the production of codeine by means of the new process hereinbefore
referred to.
EXAMPLE A.
Into a cooled solution, in ether, of one molecular proportion of diazo methane
(which compound can be determined by means of iodine solution), one molecular
proportion of morphine, either in a finely powdered state, or in an absolute
methylic or ethylic alcoholic solution, is introduced. A development of nitrogen
takes place, the solution being discolored. By evaporating the solvent, codeine
is produced, which is purified in the usual manner.
When the methylation of morphine is carried out in the presence of alkalies,
the following process may be employed, the parts being by weight.
EXAMPLE B.
:
285 parts of morphine are dissolved in 300 parts of a 35 per cent, potassa lye.
To this liquid, an ethereal solution of diazo methane is gradually added in small
quantities, the mass being energetically stirred. After the addition of each
quantity of diazo methane, a devolpment of nitrogen takes place, and a. fresh
quantity is not added until no further development of nitrogen takes place. The
addition of diazo methane is continued until morphine is no longer found to be
contained in the re-action mixture. When this stage is reached, the mixture is
extracted by means of benzene. On evaporating the benzene solution thus
obtained, the codeine separates in a crystalline state.
Instead of acting on morphine with diazo methane in a free state one can also
employ the latter in the so-called statu nascendi, that is to say, in the place of the
free diazo methane, such ingredients can be used as are capable of yielding the
said compound. Thus, for instance, nitroso methylurethane, with the addition of
alkalies, can be employed as a generator of diazo methane.
In order to illustrate this manner of proceeding, the following example is
given, which is merely typical.
The parts are by weight.
EXAMPLE C.
285 parts of morphine and 132 parts of nitroso methylurethane are, dissolved in
1000 parts of methyl alcohol. A solution of 50 parts of potassium hydroxide in
800 parts of methyl-alcohol, is then allowed to flow slowly into this mixture, which
is continuously stirred the while. When the whole solution is added, the methyl-
alcohol is evaporated, and the residue thus obtained is extracted by means of
benzene. The codeine crystallizes from the benzene solution on its evaporation.
My foreign Correspondents do not confine themselves to the particulars given in
the foregoing Specification, as these can be varied within wide limits. Thus,
for instance, instead of alcohol, benzene, and ether, other suitable solvents for
morphine, diazo methane, and nitroso methylurethane, can be employed, and, in
the place of potassium hydroxide, other alkalies can be used which act in the
same, or in a similar manner, such as sodium hydroxide, caustic ammonia,
pyridine, and the like, dissolved in a suitable solvent. Such or similar modifi-
cations do not alter the nature of this invention, which in general relates to the
production of codeine by treating morphine with diazo methane, which may be
used either in a free state, or in the so-called statu nascendi.

page_text: Having now particularly described and ascertained the nature of the said
invention and in what manner the same is to be performed, I declare that what I
claim is :-
1. The production of codeine from morphine and diazo methane or such
ingredients as are capable of yielding diazo methane.
2. The process for producing codeine, which process consists in acting with
diazo methane on morphine, in or without the presence of alkalies.
3. In the process claimed in the foregoing Claim 1, the use of mitroso methyl-
urethane as a generator for diazo methane, as hereinbefore described.
Dated this 27th day of July 1897.
NEWTON & SON,
Agents for the Applicant.