CA1244825A - Process for the dealkylation of alkaloids and intermediates - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A process for the dealkylation of 14-hydroxy-morphinan alkaloids is described. This process consists in reacting a 14-hydroxymorphinan derivative with excess ethyl chloroformate, in the presence of potassium carbonate and in a solvent, and in then subjecting the resulting carbamate to hydrolysis in a strong acid medium. Novel intermediates also are described.

Description

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Process for the dealkylation o~ alkaloids and inter-mediates On account of its exkremely high toxicity, thebaine, an alkaloid extracted from poppies or opium, does not have properties which can be used in therapy.
On the other hand, through a series of chemical reactions, it is possible to convert thebaine to a variety of substances possessing valuable therapeutic properties, principally analgesic properties and/or antagonistic properties towards opiates.
Among these substances, there may be mentioned the compounds of the formula:
HO ~

~. ~ ~ ~ N Rl ""~/ \~
¦ ¦ OH

namely:
15 naloxone 1 H2CH CH2 R2 =
naltrexone Rl = -CH2 ~ 2 nalbuphine R = -CH ~ R = ---OH
nalmefen Rl = -CH2 ~ R2 = CH2 which are all derivatives of 14-hydroxymorphinan.
As the substituent which these compounds carry on the nitrogen atom is different from that carried by thebaine (methy] group), it seems that the demethylation of the tertiary amine of thebaine constitutes an obligatory step of all these syntheses.
The demethylation of thebaine, before any other ~2,~ 5 conversion, can only be carried out with low yields due to the instability of the starting material and especially to that of the demethylated product obtained.
Therefore, this process cannot be used industrially.
On the other hand, thebaine can be converted by known processes to 14-hydroxy derivatives:

RO ~

', ~ N---C~3 '~",/ ~
~ 1 OH
0~

which are called 14-hydroxydihydrocodeinone, or oxy-codone, when R = CH3, and 14-hydroxydihydromorphinone, or oxymorphone, when R = H.
These are the starting molecules for the de-methylation of the nitrogen. However, to prevent un-desirable reactions, it is necessary for the hydroxyl or hydroxyls present in the molecule to be protected.
Most commonly, the corresponding ester will be formed by reaction with acetic anhydride. In this case, the 14-acetoxy group causes significant steric hindrance which considerably limits the demethylation possibili-ties.
It is for this reason that different reagents proposed for the demethylation of alkaloids, especially in the~morphine series, only give mediocre yields with 14-hydroxymorphinans, isolation of the demethylated comp~ound thus requ1r1ng laborious separations.

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8;~5 This is the particular case of phenyl chloro-formate, trichloroethyl chloroformate and alpha-chloroethyl chloroformate.
In the case of 14-hydroxymorphinans, only two reagents have so far been used. The first of these reagents is cyanogen bromide, which was mentioned by J. VON BRAUN, Berichte 47, 2312 (1914), in the morphine series and used by M. LEWENSTEIN, U.S. Patent ~o. 3 254 088, in the 14-hydroxymorphine series.
This reagent provides yields of the order of 70% of demethylated product. It is extremely toxic and its use in industry demands very great precautions.
The second of these reagents is vinyl chloro-formate, which was proposed by R. OLOFSON (U.S. Patents Nos. 3 905 981 and 4 141 897). With this reagent, the yield of demethylated product varies from 70 to 85%.
This reagent has two important disadvantages from the industrial point of view: on the one hand its in-stability, which leads to variable yields, and on the other hand its difficult preparation, which results in a high cost.
According to the present invention, it has been found that, surprisingly, the nitrogen of 14-hydroxy-morphinans can be demethylated using ethyl chloroformate as the reagent.
This reagent has already been used as an N-demethylating agent for alkaloids. As long ago as 1921, J. GADAMER and F. KNOCH, Arch. Phar. 259, 135-158-(1921), studying the action of ethyl chloroformate on N-methylated alkaloids, concluded that morphine, codeine and heroin were not cleaved.
More recently, E. JUCKER and A. LINDENMANN
(Swiss Patent No. 4~2 318) and G. KRAISS and K. NADOR
(Tetrahedron Letters 1, 57-58, 1971) have mentioned the use of ethyl chloroformate as a demethylating agent for 8~5 the nitrogen of derivatives of the tropane family. The yields obtained are rather low.
M, ABDEL-MONEN and P. PORTOGH~SE, J. Med. Chem.
15(2), 208-210 (1972), demethylated morphine and codeine by reaction with ethyl chloroformate, the yields being of the order of 40%.
Similarly, K. RICE and E. MAY, J. Heterocyclic Chem.14, 665 (1977), arrive at the same conclusion.
Finally, M. SCHWARTZ and R. WALLACE, J. Med.
Chem. 24, 1525-1528 (1981), react ethyl c-hloroformate with codeine to form N-ethoxycarbonylcodeine, which is then subjected to a whole series of reactions in order to convert it to the 14-hydroxymorphinan deriva-tive, which is then hydrolyzed to the corresponding N-nor derivative.
In view of the known difficulties, referred to above, in demethylating 14-hydroxymorphinans, none of these documents was able to anticipate favorable results from the use of ethyl chloroformate to demethylate oxycodone or oxymorphone.
Nevertheless, quite unexpectedly, the results obtained with ethyl chloroformate show the superiority of this reagent over those used hitherto.
In the process forming the subject of the present invention, the N-ethoxycarbonyl derivative is formed by reacting excess ethyl chloroformate with the derivative to be demethylated, in the presence of potassium carbonate and in a solventj preferably methylene chloride or chloroform under reflux. The N-ethoxycarbonyl derivatives of 14-acetoxydihydronor-codeinone and 14-acetoxydihydronormorphinone are new and constitute key intermediates in the present process;
in this respect they form part of the invention. The process of the invention is illustrated by the scheme below:

~2, ~825 R)O~

/ ~ ClCO-OCH2CH3 \ ~ N--CR3 O--C8~ C~3 C--oC ~ H s ( 2 ) R ' = CH3 or COCH

R O~l//~

O~ H

V ~ R = CH3 or H
(3) ` ~ ~

~4~1B;25 ~ he carbamate is hydrolyzed in a strong acid medium, in particular by means of ~ulfuric acid with a concentration of between S and 10 N. It is preferred to use an acetic acid/sulfuric acid mixture under reflux, this mixture producing less degradation than sulfuric acid by itself. Hydrolysis of the carbamate is accompanied by saponification of the acetate ester or esters present in the molecule.
The non-limiting example which follows will provide a clearer understanding of the invention.
A) N-Ethoxvcarbonyl-14-acetoxydihydronorcodeinone

(2) R' = CH
A mixture of 28 g of 14-acetyloxycodone [(l) R~=
CH3], 12.5 g of potassium carbonate and 45 ml of ethyl chloroformate in 30 ml of chloroform is heated under reflux for 21 hours.
After cooling, the reaction mixture is washed ~ith 150 ml of water. The aqueous phase is separated off and re-extracted twice with 50 ml of chloroform.
The chloroform extracts are combined and evaporated to dryness. This gives a brownish oil which is used as such for the next operation.
If appropriate, an analytical sample of the product can be prepared by dissolving the oil in methanol under reflux. Crystals separate out on cooling and are filtered off and washed with isopropyl ether.
After drying, m.p.: 146-147C
Thin layer chromatography: only 1 spot (benzene/acetone, 70/30 vol/vol) Elemental analysis:
Calculated: C : 63,60 H : 6.07 N : 3.37 Found: C : 63.61 H : 6.04 N : 3~28 B) Noroxycodone (3) R ~ CH3 The oil obtalned above is taken up in 30 ml of .
: :
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~ Z 5 acetic acid, after which a mixture of 20 ml of 36 N
sulfuric acid and 140 ml of water is added. The re-action mixture is heated under re1ux for 21 hours.
After cooling, its pH is brought to 11 by the addition S of a 30~ solution of sodium hydroxide, the temperature of the mixture being kept at about 25C by cooling.
100 ml of chloroform are added and the mi~ture is cooled to 0C and filtered in the presence of a filter aid. The cake is washed twice with 100 ml of chloro-form. The chloroform is decanted and the aqueousphase is extracted 3 times with 100 ml of chloroform.
The chloroform extracts are combined and evaporated to dryness in vacuo.
The solid residue is taken up in a mixture of 15 ml of acetic acid and 150 ml of water. The solid is dissolved by heating to 35-40C and the solution is then rendered alkaline by the addition oE aqueous ammonia with cooling to 20C. The solid is filtered off, washed with water until the washings are neutral, and dried in an oven at 80C.
This gives 21.6 g of noroxycodone.
M.p.: 160C (with decomposition).
Yield: 92% for the 2 steps overall.
This product is identical in every respect to an authentic sample of noroxycodone.
The process according to the invention there-fore gives particularly~advantageous results.
In order to show the superiority of this pro-cess, the operation described in paragraph A) of the example, i.e. the formation of the carbamate, was repeated except that the nature of the chloroformate , used was varied.
The quantity of starting material not converted to carbamate was determined in each case by extraction w1th d1~lu~e hydrocrloric acid.

The results obtained are shown in Table 1 below:

Chloroformate used Oxycodone not con-verted to carbamate %
Ethyl chloroformate ClCOOC2H5 4 Trichloroethyl chloro-formate ClCOOCH2-Cl~ 40 Alpha-chloroethyl chloro-formate ClCOOC,H-CH3 26 Allyl chloroformate ClCOOCH2CH=CH~ 30 _ _ .
Vinyl chloroformate ClCOOCH=CH 7 Methyl chloroformate .
ClCOOCI~3 . 13 These r~esults clearly show that, ln the re-action of a 14-hydroxymorphinan with a chloroformate to form the corresponding carbamate, the best degree of conversion is obtained with ethyl chloroformate.
This degree of conversion is sufficiently high for it not to be necessary to purify the carbamate prior to acid hydrolysis.: The latter leads dlrectly, and with a high yield, to a pure product after a single crystallization. ~ ~
.
Furthermore, the process according to the lS invention has the following advantages:
- the us~e of a perfectly stable reagent, ethyl chloroformate, which makes it possible, inter alia,: to obtain reproducible yields;
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- the use of a reagent of lower toxicity than those used hitherto, namely cyanogen bromide and vinyl chloroformate; and - the use of a reagent which is inexpensive on account of its easy preparation.

Claims (5)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the dealkylation of 14-hydroxy-morphinan alkaloids, which consists in:
1) reacting the 14-hydroxy derivative of the formula:

in which R' is CH3 or COCH3 9 with excess ethyl chloro-formate, in the presence of potassium carbonate and in a solvent, and 2) subjecting the resulting carbamate of the formula:
(2) in which R' is CH3 or COCH3, to hydrolysis in a strong acid medium to give the corresponding dealkylated derivative of the formula:
(3) in which R is CH3 or hydrogen.

2. The process as claimed in claim 1, wherein the first step is carried out in methylene chloride or chloroform under reflux.

3. The process as claimed in one of claims 1 or 2, wherein the hydrolysis is carried out with sulfuric acid.

4. The process as claimed in one of claims 1 or 2, wherein the hydrolysis is carried out with an acetic acid/sulfuric acid mixture under reflux.

5. As intermediates useful in the process as claimed in claim 1, the N-ethoxycarbonyl derivatives of 14-acetoxy-dihydronorcodeinone and 14-acetoxydihydronormorphinone of the formula:

(2) in which R' is CH3 or COCH3.