Sinomeninic acid

Like other a-diketones and or o-quinones, e.g. dibenzoylsinomenol-quinone [15], sinomenine hydrate [lxvii behaving as lxvih, R = II] on heating with 30 per cent, hydrogen peroxide in glacial acetic acid is oxidized to a dibasic acid, sinomeninic acid [xo, R = H], This on bromination gives 1-bromosinomeninic acid [xc, R = Br], also obtainable by the oxidation of 1-bromosinomeninone [Lxvm, R = Br] [73]. (—)-1-bromosinomeninic acid can be prepared by the oxidation of (—)-1-bromosinomeninone it can be reduced catalytically to (—)-sinomeninic acid [74]. These acids exist as lactones. 

When sinomenine is heated with hydrochloric acid and the product treated with ammonia solution, Z)w-demethylsinomenylidene, (CjgH,jO,N), is formed,which crystallises from chloroform, has m.p. > 312°,... 

The mixture of bases is best obtained by mixing solutions of sinomenine hydrochloride and potassium ferricyanide and adding solution of sodium carbonate. The precipitate is collected, washed with water and dissolved in dilute hydrochloric acid. The mixed hydrochlorides, which crystallise out, are separated by repeated crystallisation from water, the i/i-sinomenine hydrochloride remaining in the mother liquors. 

Tuduranine, CjgHjgOgN. This member of the aporphine group (p. 306) is the most recent addition to Sinomenium alkaloids and was isolated by Goto from the mother liquors of sinomenine. It is crystalline, has m.p. 125° (with softening at 105°), and yields a sparingly soluble hydrochloride, m.p. 286° (dec.), [a] f — 148° (dilute MeOH), is freely soluble in alkali, and gives feeble ferric chloride and diazo-colour reactions and a fuchsin-red colour with formaldehyde and sulphuric acid. It behaves as a secondary base and yields a diacetyl derivative, m.p. 170°, [a] / — 321-71° (MeOH), which does not form a methiodide, but can be hydrolysed to A -acetyl-tuduranine, m.p. 277°, — 395-24°, and this can be methylated to... 

Dihydrothebainone [ix], obtained by the catalytic reduction of thebainone-A [v] [1] and thebainone-B [xm] [13], can be most conveniently prepared by the catalytic reduction of thebaine in acid solution [9-12, 25], and it can also be obtained by the hydrolysis of its two enol ethers (see below). It is a phenolic, ketonic, base, that shows the diazo-reaction in dilutions up to 1 in 2,000,000 [26-27], gives a methyl ether [28], oxime [9], semicarbazone [29], and a benzylidene [30] and piperonylidene [25] derivative. The optical antipode is produced by the sodium amalgam reduction of sinomenine [xxvi] and is known as desmethoxydihydrosinomenine [31]. 

The reduction of sinomenine with glacial acetic acid and sodium amalgam gives a dimolecular phenol (Ci8H2403N)2 H20 about which nothing further is known [24],... 

Sinomenine ac/tromethine [xxvin] (initially called N-methylanhydro-sinomenine [17]) is obtained when sinomenine methiodide is heated for one minute with two equivalents of 2 per cent, aqueous sodium hydroxide. It cannot be recrystallized, even from alcohol, and is best purified through the sodium salt. The name is assigned as a result of the faint yellow halochromism of a solution of the base in concentrated sulphuric acid. Like sinomenine it gives sinomenol and dibenzoylsino-menol on heating with 66 per cent, potassium hydroxide and benzoic anhydride respectively [38]. 

Sinomenine m oZeomethine [xxx] (initially called sinomenine a-methine [17]) is obtained in 20 per cent, yield when sinomenine achro-methine is heated with 10 per cent, sodium hydroxide [38] and also, in low yield, when sinomenine methiodide is degraded [17]. Its methio-dide, formed in almost quantitative yield by the action of cold 10 per cent, sodium hydroxide on sinomenine ac romethine methiodide, is degraded by hot alkali to sinomenol. Sinomenine w oZeomethine gives an intensely blue halochromic solution in concentrated acid solution [38], The thebainone analogue, thebainone-B methine [xxxi], has also been prepared [39],... 

Hydrolysis of the enol ether may be achieved by 2N hydrochloric acid at 100° C., and if the solution is neutralized with sodium carbonate sinomenine hydrate [lxvh] is precipitated. This apparently exists in the hemiacetal form, but the 7-methoxyl group is readily lost and for all practical purposes sinomenine hydrate behaves as the a-diketone sino-meninone [Lxvm, R = H], and gives a dioxime and disemicarbazone [61]. 

Hydrolysis of the enol ether group of sinomenine is apparently not effected by concentrated sulphuric acid below 10° C., as sinomenine under these conditions gives sinomenine-1-sulphonic acid [lxxvii]. Sinomenine hydrate on treating in this way loses the 7-methoxyl group, the product being sinomeninone-1-sulphonic acid [Lxxvm]. Sinomenine derivatives with position 1 (i.e. para to the phenolic group) substituted, e.g. 1-bromosinomenine and disinomenine (see below) cannot be sulphonated in this way [67-68]. 

Methylsinomeninic acid [xci, R = H] and 1-bromomethylsinome-ninic acid [xci, R = Br] are formed when methylsinomeninone [73] and 1-bromomethylsinomeninone [44] respectively are oxidized with hydrogen peroxide. Similarly the oxidation of 1-bromosinomeneine ketone [lxxvi] affords 1-bromosinomeneinic acid [xcii] [73]. The ultraviolet absorption spectra of [xc, R = H], [xc, R = Br], and [xci, R = H] are very similar to that of sinomenine hydrate, which in turn is almost identical with that of sinomenine [73]. 

Bromosinomeneine ketone [lxxvi]. can be made to undergo the benzil —> benzilic acid transformation in hot alkali, the product being 1-bromosinomenilic acid [xcm]. This acid is also obtained when the amorphous product of bromination of 1-bromosinomeninone with one equivalent of bromine is treated with alkali, and from sinomenine hydrate and one equivalent of bromine [69]. 

The strong diazo-reaction evident with sinomenine is greatly diminished in the two bimolecular alkaloids as it is in 1-bromosinomenine, and further support for the hypothesis of a 1 T linkage in disinomenine and -disinomenine is provided by the facts that 1-bromosinomenine cannot be oxidized to a dimolecular base [78] and that disinomenine cannot be sulphonated by cold concentrated sulphuric acid, unlike sinomenine which is converted to sinomenine- 1-sulphonic acid [67-68],... 

Dibenzoylsinomenol and 4 6-diacetylsinomenol can be oxidized with chromic acid to dibenzoyl- and diacetylsinomenolquinones, [xciv, R = CO] and [xciv, R = Ac] respectively, without loss of groups [98, 103], showing that in sinomenine the oxygen substituents are not located at C-9 or C-10. The quinone esters can be hydrolysed to sino-menolquinone [xciv, R = H] and converted to dhnethylsinomenol-quinone [xcrv, R = Me] and diethylsinomenolquinone [xciv, R = Et] [103]. 

The positions of the oxygen substituents in sinomenine was demonstrated by the identity of dimethylsinomenol [xcvil] with 3 4 6 7-tetramethoxyphenanthrene. This was synthesized by Pschorr s method from 2-nitroveratric aldehyde and 3 4-dimethoxyphenylacetic acid, a synthesis that afforded two tetramethoxyphenanthrene-9-carboxyhc acids, [xcvm] and [xoix], one of which, [xcvm], being also accessible from the bromo-acid [c] must be the 3 4 5 6-isomer the other [xcix], which must therefor be the 3 4 6 7-isomer, gave dimethylsinomenol on decarboxylation [103, 105-6],... 

In an analogous manner 3-hydroxy-N-methylmorphinane [nxxm] was prepared from [lxxii], and when [lxxiv] was heated with hydrochloric acid at 120° C. cyclization and partial demethylation occurred, the product being dl-tetrahydrodesoxycodeine [lxxv], identical with the racemate prepared from the separate d and l isomers obtained from sinomenine and codeine respectively. The racemate was resolved by d-tartaric acid [24], Complete demethylation occurred when the cyclization was effected with hydrobromic acid, the product being dZ-tetrahydrodesoxymorphine [24],... 

Methoxycodeine (154) has been prepared from l-bromo-(—)-sinomeninone (151 R = Br) via l-bromo-(+)-sinomenine (152), which on bromination and cyclization with alkali yields l-bromo-7-methoxycodeinone (153) this, on reduction with lithium aluminium hydride, yields (154). This derivative of codeine is an orally active analgesic, in spite of the fact that it is unstable to acids, which convert it into the inactive (-)-sinomeninone (151 R = H). ... 

A greatly improved conversion of (-)-sinomenine into (+)-morphine with an overall yield of 28% has been recorded. Reduction of sinomenine to sinomenol followed by treatment with polyphosphoric acid gives (+)-dihydrocodeinone, the dimethyl ketal of which suffers elimination of methanol to give dihydrothebaine, which can be converted by standard procedures into (+)-codeinone, and hence into (+)-codeine and (+)-morphine. 

Vitamin B12 (catalysis) ascorbic acid morphinan alkaloids (morphine, sinomenine, and codeine) pyridoxine sodium nitroprusside sulbactam sodium (enhanced CL) clavulanic acid (enhanced CL) captopril (enhanced CL)... 

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