United States Patent ~Office
`
`2,806,033
`Patented Sept. ·to, 1957
`
`1
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`2,806,033
`MORPHINE DERIVATIVE
`Mozes Juda Lewenstem, Kew Gardens, N.Y., and Ulrich
`Weiss, Jamaica, N. Y.; said Weiss assignor to said
`Lewenstein
`No Drawing. Application August 3, 1955,
`Serial No. 526,308
`6 Claims. (Cl. 260-285)
`
`This invention relates to a new morphine derivative of
`extremely high analgesic activity and has particular rela(cid:173)
`tion to a dihydromorphinone substituted by an -OH
`group in the molecular position shown in the structural
`formula further below. The invention also relates to the
`process for preparing the new morphine derivative and to
`salts of this derivative.
`Ever since morphine was first isolated and used for
`the alleviation of pain, the need has been felt for an
`even more potent analgesic. Morphine, when adminis(cid:173)
`tered in recommended doses, produces relief of pain in
`many conditions. However, its effect is often found in(cid:173)
`sufficient in biliary and renal colics, the terminal stages
`of cancer and in other instances. It is not advisable to
`increase the dose, because of the depressing influence of
`morphine on respiration and heart rate. A number of
`morphine derivatives and synthetic compounds having
`morphine-like action have been made available in recent
`years, but the need for an analgesic which will relieve even
`most severe pain has persisted. The main object of the
`invention is to provide a new compound of powerful ef(cid:173)
`fect and satisfactory chemical stability.
`Another object of the present invention consists in pro(cid:173)
`viding a precess for preparing this compound. Further
`objects and the advantages of the invention will be ap(cid:173)
`parent from the appended claims and the following spec(cid:173)
`ification which describes, by way of example, some em(cid:173)
`bodiments of the invention.
`The new compound of our present invention corresponds
`to the following structural formula:
`NCH,
`n,c-c~ 1 H
`"-. C '
`H
`/
`"
`C-C
`HOC±CH1
`~ """
`" /
`"
`/
`C-C-- Ho CHo
`HC
`/
`C=C-0-CH-CO
`~)H
`We have found that this compound can be prepared from
`14-hydroxydihydrocodeinone by treating the latter with
`aqueous hydrobromic acid under the conditions described
`It is
`hereinafter. This result could not be expected.
`true that many codeine derivatives, including a number of
`ketonic ones, have been demethylated to the corresponding
`morphine derivatives; however, the chemical literature
`does not show any case in which this reaction was ap(cid:173)
`plied successfully to a codeine derivative containing a ter(cid:173)
`tiary hydroxyl group. By choosing the method described
`hereinafter we have found it possible to remove the meth(cid:173)
`yl group from 14-hydroxydihydrocodeinone without ad(cid:173)
`ditional changes in the molecule and thus obtain 14-hy(cid:173)
`droxydihydromorphinone. We have found that the con(cid:173)
`ditions described hereinafter are essential for avoiding
`side reactions and for the formation of a crystallizable
`product.
`
`Example
`90 ml. of concentrated hydrobromic acid are heated to
`
`35
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`2
`90° C. 9 grams of 14-hydroxydihydrocodeinone are then
`added under stirring and the mixture is quickly heated to
`116° C. and kept at this temperature under reflux con(cid:173)
`denser for 20 minutes, with continued stirring. The re-
`5 suiting brown solution is diluted with about 90 ml. of
`water and chilled with ice. Aqueous 10% sodium hy(cid:173)
`droxide solution is now added to alkaline reaction and
`the liquid is extracted 3 times with 100 cc. portions of
`chloroform. The layers are separated and the aqueous
`10 phase is filtered and acidified by the addition of concen(cid:173)
`trated aqueous hydrochloric acid, treated with charcoal
`and filtered. The filtrate is treated with concentrated
`aqueous ammonia until the mixture gives a pink color
`on phenolphthalein paper. The liquid is extracted 7
`15 times with 100 cc. portions of .chloroform, the extracts
`are combined, dried with anhydrous s.odium .sulfate arid
`evaporated. The residue is dissolved in ethanol by reflu:x(cid:173)
`ing and the ethanol evaporated nearly to dryness. 100
`cc. of benzene are then added, the mixture is reflu:xed for
`20 Vz hour and set aside for crystallization. After cooling,
`the desired compound is collected by filtration. 2.3 grams
`of a white crystalline powder are obtained; M.P. 245-247°
`C. This powder consisting of 14-hydroxydihydromorphi(cid:173)
`none can be purified by recrystallization from benzene,
`25 ethylacetate or ethanol. From benzene it generally forms
`diamond shaped platelets, while needles are obtained
`from ethylacetate.
`On heating, the crystals are discolored from about 200 o
`on, and melt at 246-247° to a black liquid, which de-
`30 composes with strong volume increase, if the tempera(cid:173)
`ture is raised further by a few degrees.
`Elementary analysis of the compound agrees well with
`the formula C17H19N04, corresponding to the structural
`formula given above.
`In the foregoing example, the reaction mixture may be
`heated at 105 o to 120 o C. for from 20 to 50 minutes, the
`time of reaction depending upon the temperature em(cid:173)
`ployed.
`The phenolic nature of the base is shown by its reac-
`40 tion with ferric chloride. Addition of one drop of aqueous
`FeCia solution to an aqueous suspension of the pure
`compound produces a beautiful blue color. Furthermore
`the base dissolves readily in dilute aqueous NaOH, giv(cid:173)
`ing a clear, colorless solution. Addition of an alcoholic
`45 solution of m-dinitrobenzene to the alkaline liquid pro(cid:173)
`duces a pink to red color; this reaction is considered to in(cid:173)
`dicate the presence of the group -CO-CH:r-. The con(cid:173)
`stitution of the compound as 14-hydroxydihydromorphi-
`50 none is proven not only by the reactions described above,
`but in addition by its methylation with diazomethane,
`which readily reconverts the compound to 14-hydroxy(cid:173)
`dihydrocodeinone. Mixed melting points of this com(cid:173)
`pound vlith the starting material and of the hydrochlorides
`55 and the oxims of both products did not show any depres(cid:173)
`sion. This proves that in the heating of 14-hydroxydi(cid:173)
`hydrocodeinone with concentrated HBr no structural
`change beyond the demethylation has taken place. 14-
`hydroxydihydromorphinone forms a crystalline, non-hy-
`60 groscopic hydrochloride; other salts, of any organic or
`inorganic acid can be prepared in conventional manner,
`for example the bromide, iodide, sulfate, phosphates, such
`as orthophosphates and metaphosphate, nitrite, nitrate,
`bitartrate, salicylate, terephthalate, acetate, propionate,
`65 phthalate, benzoate, camphosulfonate, citrate and others
`can be prepared.
`The new compound of the invention and its salts, can
`be used as analgesics, if desired in mixture with other
`therapeutically active substances, for example other
`70 analgesics and other therapeutic agents.
`It has been stated in the art that attempts to demethyl(cid:173)
`ate dihydrohydroxycodeinone with 48% hydrobromic acid
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`1
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`-~,806,033
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`3
`or .ihydriomc ilteid resulted. jn non-crystalline products.
`This ..cannot .he ..considered .. a .showing _of _14"-dihydrohy(cid:173)
`droxymorpbinone or an attempt to prepare 14-dihydro(cid:173)
`hydroxymorpbinone in view of the absence of any case
`:in 'the :art, ·:in· :which ::a :rirorpbine derivative ·contaiilirrg a 5
`:tertiary _;alcohol•· group :could ·be demethylatea with· an
`-acid .withoutother ·structural- changes.
`Reference is :made :to :our co-pending: application filed
`in our names.under'Serial.No. 228,978.on May 29, 1951,
`·of, which this~isca continuation-in-part.
`What >is<clainied •is:
`1. As a ·new :compound 14-hydroxydihydromorphi(cid:173)
`:none ·consisting :of:a:crystalline· substance having a melting
`·pointoL245•..;.247• C.
`2. :As a c11ew ~compoimd a ·salt of J4~hydroxydihydro- 15
`,morphinone.
`:3. As,'a new compound :14-hydtoxydihydromorphinone
`'hydrochloride. ·
`·4. :A new compourid:selected from the group of 14-hy(cid:173)
`':droxydihydromorphinone consisting of a crystalline sub- 20
`
`4
`stance haVing a melting point of 245°-247° c. and its
`..salts.
`5. A process for preparing 14-hydroxydihydromorphi(cid:173)
`none, comprising heating 14-hydroxydihydrocodeinone
`with concentrated aqueous HBr to a temperature slightly
`below the boiling point; diluting the reaction mixture
`with water and cooling the diluted mixture; rendering the
`cooled solution alkaline and extracting it with chloroform;
`acidifying the ·aqueous phase and subsequently adding
`10 .thereto ammonia to alkaline reaction;. and extracting the
`reaction·product from ·the liquid with chloroform.
`6. A process as claimed in claim 5, in which the chloro(cid:173)
`form extract is evaporated and the residue is treated with
`alcohol.
`
`References Cited in the file of this patent
`Lutz et al.: J. Org. Chemistry, vol. 4, pp. 220-228,
`1939.
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