DE260233C - - Google Patents

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—.Te 260233 CLASS 12j ?. GROUP

The present invention relates to a method for preparing hydrogenated alkaloids of the morphine group. The method consists in that one alkaloids of the morphine group in The presence of colloidal palladium as a catalyst is reduced with molecular hydrogen.

The reduction is quick and smooth,

and the hydrogenated alkaloids thus obtained

ίο the morphine group point towards the not hydrogenated starting materials have new valuable properties in therapeutic terms.

Example i.

Hydromorphine:

0.1 g colloidal palladium is dissolved in 10 ecm of water and shaken with hydrogen until saturation; then 10 g of morphine chlorohydrate (dissolved in 250 ecm of water) are added and the vessel is shaken further until the calculated amount of hydrogen has been absorbed. Then 1 ecm in sulfuric acid is added, left to stand for a few hours until the palladium has flocculated quite finely, then filtered and the filtrate made alkaline with soda. After a short time, the new base separates out in the form of fine, almost colorless needles which have the composition C _{] 7} H ₂₁ NO ₃ 'H ₂ O. the end

hot methyl or ethyl alcohol crystallizes the hydromorphine in very fine needles, those between 155 ° and 157 ° with decomposition melt and contain 1 molecule of water of crystallization, which they also hold when standing in the Do not lose the vacuum desiccator. From hot acetone or a lot of hot chloroform this becomes Hydromorphine in fairly large prisms, from a lot of hot benzene in microscopic ones Obtain prisms of the same melting point.

It has the same bitter aftertaste as morphine and gives in to the reactions Fröhde, Husemann, Marquis and with ferric chloride in the same way; Silver nitrate is reduced immediately.

The hydrochloride is prepared by dissolving the hydromorphine in dilute hydrochloric acid and carefully evaporating the solution. Of course, it can also be obtained directly from the above-mentioned reduced and palladium-free solution of the morphine chlorohydrate by evaporation. The salt is thus obtained in microscopic prisms which are easily soluble in water and which have the composition C ₁₇ H ₂₁ NO ₃ - H Cl .

The sulfate prepared in the same way is difficult to obtain in crystallized form.

With regard to the reduction on a larger scale, it turned out that ζ. B. 25 g Morphine chlorohydrate dissolved in 500 ecm of water with the help of only 0.04 to 0.05 g of colloidal Palladium can be reduced quantitatively in about 80 to 90 minutes.

It has also been found that in the reduction of alkaloid salts in aqueous Solution are electrolytically dissociated, the initially colloidal palladium sometimes flocculates will, and often. so fine that

this precipitate settles on the ground only after many hours and with the help of good filters can be separated from the solution. However, it is through this flocculation that the end result becomes does not affect the reduction in any way; at most the speed of the Reduction slows down, which is consistent with the long-known fact that the catalytic effect of the metals

ίο platinum group, such as platinum, palladium or osmium, a special property of these elements in general and not just theirs colloidal solutions is, and that in the colloidal solutions as a result of the special fine distribution, greatly enlarged, catalytically active surface, only the speed, but does not affect the outcome of the reaction.

The removal of the catalyst after the.

Reduction can be simplified by making the solutions without the addition of an acid simply sucked off through a collodion filter with the help of a water jet pump and so completely can be obtained metal-free.

-ο · · 1

Example 2.

Hydrocodeine:

0.05 g of colloidal palladium are dissolved in 10 ecm of water and shaken with hydrogen until saturation; then a solution of 5 g of codeine chlorohydrate or phosphate in 30 to 50 ecm of water is added and the mixture is shaken until the calculated amount of hydrogen - about 300 ecm for 2 atoms of hydrogen per molecule of alkaloid salt - was absorbed, which took about 25 minutes. The solution freed from palladium as above is strongly concentrated in vacuo and the free hydrocodeine is precipitated by a concentrated solution of 2.5 g of crystallized sodium carbonate. From water or very dilute methyl alcohol is crystallized melt to 63 ⁰ in rhombic octahedra contain one molecule crystal water and, after several recrystallizations at 62 °. The color reactions according to Froh de and Hesse exist in the same way.

Analysis: 0.1664 g substance = 0.4121 g CO _Z ; 0.1162 g H ₂ O.

Calculated: Found:

C = 67.77 percent,
H = 7.66 -

67.54 percent,
7.96 -

To obtain pure hydrocodeine, it is even easier to get the free codeine directly to dissolve in water and reduce.

. Example 3.

There are 5 g of codeine in 400 ecm of water dissolved and with 0.05 g colloidal palladium exactly in the same way and just as quickly reduced like the chlorohydrate or phosphate; in this case the palladium remains colloidal in solution, since codeine or hydrocodeine as non-electrolytes do not cause any precipitation; the liquid filtered through a collodion filter is kept in a vacuum until crystallization begins concentrated and after some time the almost quantitatively excreted hydrocodeine was filtered off.

Example 4.
Tetrahydrothebaine:

2 g of thebain chlorohydrate are dissolved in 50 ecm of water and 0.1 g in the reduction apparatus added colloidal palladium saturated with hydrogen; as the palladium equals pretty much coarsely flocculated and thus its effective surface is greatly reduced, the reduction proceeds, in which in accordance with With the current thebaine formula, 4 atoms of hydrogen per molecule can be absorbed, pretty slow. It takes about 90 minutes to absorb the required 275 ecm of hydrogen necessary. In the solution freed from the palladium, the tetrahydrothebaine was replaced by a solution of 1 g of sodium carbonate or the corresponding amount of caustic soda or ammonia as an amorphous white precipitate obtain. Despite all attempts to achieve this, it has not yet been possible to achieve the in Water as good as insoluble, easily soluble in common organic solvents To keep the body crystalline. While thebaine with concentrated sulfuric acid or Fröhde's or Erdmann's reagent gives a strong red color, the hydroderivative shows a purple color that becomes quite dark when heated; on the other hand is the yellow color with concentrated nitric acid the same as with thebaine.

Analysis: 0.1858 g substance = 0.4924 g CO ₂ ; 0.1295 g H ₂ O.

Calculated C ₁₉ H ₂₅ NO ₃ : Found:

C = 72.33 percent,
H = 7.99

72.23 percent,
7.62 -.

The chlorine hydrate crystallizes from water in prisms; mineral acids make it pretty easily decomposed, so that, if you have it for a few days, for. B. stand with dilute hydrochloric acid leaves, no more hydrothebaine is precipitated by alkali.

The bitartrate (represented by reduction of thebaine bitartrate) is in cold water or alcohol rather heavy, more easily soluble in the heat.

The hydrogenation of thebaine is much faster if the free base is dissolved in alcohol dissolved, since in this case the palladium is not precipitated, but colloidal remains in solution and according to the

finer distribution has a stronger catalytic effect.

Of course, other morphine derivatives, such as those used therapeutically, can also be used Compounds Diacetylmorphine, Morphinäthylbzw. Benzyl ethers, among others, all the same Contain carbon double bond, hydrogenate in an analogous manner; examined that more closely Diacetyl hydromorphine - both through re-

induction of diacetylmorphine as represented by acetylating hydromorphine - crystallizes from absolute alcohol in fine white needles from melting point 165 to 166 °.

With regard to the therapeutic properties, for their investigation and any Application, of course, not the free alkaloids, but only their salts come into question, is due to detailed pharmacological Investigations to say:

The hydromorphine (injected as a hydrochloride in ι percent solution) has on the sensitive sphere of the cerebrum has the same effect as the morphine and not in attenuated Shape such as B. Codeine. Advantages over the morphine are that it

1. shows a longer (even if occurring a little later) effect, and that

2. Getting used to it is much harder.

For clinical use, this means that you can use a single dose can have a longer effect and that there is a risk of chronic morphinism is decreased.

With the hydrocodeine is according to the previous pharmacological investigations (Cat experiments) the excitatory effect is less pronounced than with the codeine at least same narcotic effect, this also lasts a little longer.

In contrast to thebaine, tetrahydrothebaine does not produce tetanus, at least at normal doses; while z. B. 0.5 mg thebaine cause tetanus in a frog in 5 minutes is ten times the dose Hydrothebain completely ineffective, and 50 times the dose only calls for tetanus after hours emerged. Whether the hydrothebain except for this important property that it is in much closer detail Relationship to which morphine and codeine brings other valuable therapeutic properties that could thus enable the thebaine obtained as a by-product in the morphine production to be used not yet be determined.

In the case of diacetylhydromorphine, which has also been pharmacologically examined, has also been found show the very interesting fact that with a suitable dosage the convulsive Effect is significantly weakened; z. B. produces the hydroderivative in frogs 24 hours later an increase in reflexes, which is then significantly less pronounced than that already Generated 24 hours earlier by diacetylmorphine. It follows that also at the bedside the possibility exists of the excitatory component of the non-hydrogenated alkaloid switch off if possible.

Claims (1)

Patent claim: Process for the preparation of hydrogenated alkaloids of the morphine group, consisting therein that one alkaloids of the morphine group with molecular hydrogen in the presence of colloidal palladium as Treated catalyst.