Neopine

N ic opine was first isolated by Dobbie and Lauder from the last mother liquors from the processing of the opium alkaloids after all other bases had been eliminated [1], This remains the only source of the base. The method of isolation has since been improved and the alkaloid can ho separated from codeine through the sulphates [2], The base was first allotted the formula C18H2404N and the name hydroxycodeine it was shown to contain one —OMe, one —NMe, and to be a tertiary base. Its colour reactions and ultra-violet absorption spectrum are practically idontical with those of codeine [1]. 

In general the double bond seems to be less reactive in neopine than in codeine, e.g. reduction proceeds less readily [3] and oxidation to a dihydroxy dihydro-compound cannot be effected with permanganate [fi]. Noopino is recovered unchanged from attempts to oxidize it to a kototio with chromic aoid [5]. 

Movement of the double bond does not occur during the methylation of morphine to codeine, from which reaction no neopine can be isolated [2], Unlike codeine neopine can be demethylated by hydrobromic acid and glacial acetic acid, the product being 6-acetylneomorphine [vi], probably formed by way of the 3 4-diacetyl derivative, which readily loses the 3-acetyl group in dilute acetic acid. Demethylation with 48 per cent, hydrobromic acid alone affords neomorphine [vn], also obtained by the hydrolysis of [vi], but the free dihydroxy-compound is readily soluble in water and difficult to isolate. Neomorphine is converted to neopine by diazomethane. Reduction of 6-acetylneomorphine yields 6-acetyldihydromorphine, which can be hydrolysed to dihydromorphine [6]. 

An intractable phenolic substance is produced by the prolonged boiling of neopine hydrobromide with Raney nickel in alcohol [7], Lithium aluminium hydride reduction of p-toluenesulphonylneopine gives desoxyneopine (desoxycodeine-D) [vm] [8] (see Chap. IX). 

Compound m.p. °C. recrystn. form rotation Temp. Solvent Refs. 

---

Morphine, Cl7Hig03N Codeine, CjaH2i03N Neopine, CjaH2i03N... 

Codeine corresponding to 8-methylmorphimethine is neopine that similarly related to the S-methine is still unknown. 

Neopine, C gHaiOgN. This alkaloid was discovered by T. and H. Smith in the final mother liquors obtained in the extraction of opium alkaloids, and was examined by Dobbie and Lauder, and later by van Duin, Robinson and Smith, who cystallised the base, found it isomeric with codeine and showed that it is jS-codeine (p. 251). The base crystallises from light petroleum in needles, m.p. 127-127-5°. In aqueous solution... 

Methylmospiiimethines. The principal characters of these derivatives of the four known morphines have been given already (p. 218). Below are shown formulae for the two stereoisomeric pairs of morphines and the three stereoisomeric pairs of methylmorphimethines. -Methyl-morphimethine is also neopinemethine (p. 219), and for that reason the formula of neopine is added. 

According to Eddy, as quoted by Small, the analgesic action of neopine, n omorphine, 6-acetylneomorphine or 3 6-diacetylneomorphine (p. 218) is definitely less than that of morphine and its corresponding analogues. The first two are about half as toxic as codeine and morphine respectively, and the second pair are more toxic than their morphine analogues. None of the four shows the Straub reaction and the convulsant action is less marked. 

Methods for the conversion of derivatives of morphine into their N-nor-com-pounds, using vinyl chloroformate,149 trichloroethyl chloroformate,150 and phenyl chloroformate,151 have been patented. Norneopine has been prepared from neopine and diethyl azodicarboxylate and by the hydrolysis of 7V-nitrosonor-neopine.152 The conversion of N-nor-bases into N-alkyl-compounds by the reduction of amides has been covered by a further patent.153... 

Nitrobenzene-p-sulphonyI)neopine has been converted into the 6/3-chloro- and 6j0-bromo-6-deoxy-compounds by heating with lithium chloride and bromide,154 and the 6-O-methanesulphonyl analogue gives the same products together with the A6-8-deoxy-compound, which is the sole product when the ester is heated with sodium iodide.155 2-Nitromorphine and 2-nitrocodeine have been reduced to the 2-amino-compounds in 60% and 81% yield respectively.156... 

Codeine, 14-hydroxycodeine, neopine, and O-methylflavinantine have been isolated from Papaver bracteatum,146 flavinantine and amurine from Meconopsis cambrica,113 isosinoacutine from Stephania elegans,174 and a new alkaloid, tridictyophylline, for which the structure (96) was determined by X-ray crystallography, from Triclisia dictyophylla.175 Bound morphine, codeine, and thebaine have been found in P. bracteatum and P. somniferum,176 and the effect of the period of maturation of the plants on the yield of these three alkaloids from P. somniferum has been studied.177,178 Codeine has been isolated from cell suspension cultures of P. somniferum under conditions where no morphine, norcodeine, or thebaine could be detected.179... 

Neopine (= p-Codeine) Papaver somniferum (opium O-R agonist [analgesic,... 

Methocarbamol, methotrimeprazine, morantel, neopine, noscapine (fades), pyrantel Butaperazine, dopamine, tridihexethyl... 

Alkaloid isolation and structural elucidation is summarized in Table 6. In addition to known constituents, codeine and neopine have been isolated from Papaver brac-teatum Although callus cells from this plant contain thebaine at early stages of subculturing, only traces are found later. - ° Thebaine was identified among seventeen isoquinoline alkaloids detected in, or isolated from P. syriacum. ... 

Codeine may be isolated from opium by the Gregory process [9], in which the concentrated aqueous opium extract is treated with a concentrated solution of calcium chloride, when calcium meconate, lactate, and sulphate are precipitated and removed, when the filtrate on concentration deposits the Gregory salt , a mixture of the hydrochlorides of morphine and codeine. This is purified, dissolved in water, and the morphine precipitated by ammonia, when the codeine remains in solution from which it is extracted by benzene, or the solution concentrated to the point at which a mixture of codeine hydrochloride and ammonium chloride separates. Other procedures for the isolation of codeine are available [7, 8, 10-22 inc.], critical summaries of which are given by Kanewskaja [23] and Barbier [24], Codeine may be separated from neopine (see Chap. VII) through the sulphate [25] and from morphine by chromatography [26-29]. Most of the codeine used commercially is prepared by the methylation of morphine (see below). 

Catalytic hydrogenation of codeine proceeds rapidly with saturation of the 7 8 double bond and formation of dihydrocodeine [m, R = OH] [267-9], also obtainable by the electrolytic reduction of codeine [270], the catalytic reduction of neopine [xm] [271], the methylation of dihydromorphine [272], and the catalytic reduction of dihydro-codeinone [xiv] [273]. By the latter method the optical antipode of dihydrocodeine may be prepared from the sinomenine series [274-5] (see Chap. XXVII). Both enantiomorphs can be demethylated to the corresponding dihydromorphines [269, 274-5]. Dihydrocodeine methyl ether is identical with tetrahydrothebaine [276-8] (see Chap. XIII). 

Alkaline degradation of codeine methiodide affords a-codeimethine [xxi] [185, 285], which can be isomerized by alcoholic alkali to /3-codeimethine [xxn] [187, 286-7], also obtainable by the degradation of neopine [xm] methiodide [271]. The degradation of codeine ethiodide follows a similar course [288]. These bases suffer dehydration and loss of the basic side-chain when heated with acetic anhydride and sodium acetate (when acetylmethylmorphol [xxm] is formed [187, 289-90]), and when subjected to further Hofmann degradation (which leads to methylmorphenol [xxiv] [290-2]). The resulting aromatic phenan-threne derivatives are of considerable importance in the elucidation of the basic structure of the morphine alkaloids and are discussed in detail in Chapter XXVII. 

---