Demethylation chloroformate

Hydrocupreine (Dihydrocupreine), CigH2402N2. This alkaloid does not occur naturally, but can be produced by demethylating dihydroquinine or reducing cupreine. It crystallises from dilute alcohol in minute needles or from a mixture of chloroform and benzene in warty masses, m.p. 230° (dec.) with some sintering at 185-200°, is readily soluble in chloroform, alcohol or hot benzene, and much less so in ethyl acetate, insoluble in light petroleum, — 155-5° (G. and Wi ° 148-7°... 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

The last monomeric alkaloid, Nl-demethyl- 16-epiaccedine (24, C19H24N202, MP 170-172°C, [a]D +50°), existed as an equilibrium mixture of carbinolamine and open-chain carbonyl forms in which the latter are present in amounts of 10% in MeOH and 25% in chloroform. Hofmann degradation of 24 methiodide... 

Finally, a third way of synthesis is from imipramine (7.1.1), which nndergoes demethylation by snccessive reaction with ethyl chloroformate, giving 5-[3-(Af-carbethoxy-iV-methyl)aniino-propyl]-10,ll-dihydro-5H-dibenz[b,f azepine (7.1.15), the alkaline hydrolysis of which leads to desipramine (7.1.13) [23,24],... 

The original synthesis of duloxetine (3) is relatively straightforward, involving a four-step sequence from readily available 2-acetylthiophene 30 (Scheme 14.7). Understandably, the main synthetic challenge stems from the presence of a chiral center, because duloxetine (3) is marketed as the (5)-enantiomer as shown. Thus, a Mannich reaction between 30 and dimethylamine generated ketone amine 31, which was then reduced to provide intermediate racemic alcohol amine 32. The desired optically active (5)-alcohol 32a was accessed via resolution of racemate 32 with (5)-(+)-mandelic acid, which provided the necessary substrate for etherihcation with 1-fluoronaphthalene to afford optically active amine 33. Finally, A -demethylation with 2,2,2-trichloroethyl chloroformate and cleavage of the intermediate carbamate with zinc powder and formic acid led to the desired target duloxetine (3). 

As early as 1938, Shorygin and Topchiyev [10] nitrated dimethylaniline with a solution of nitrogen dioxide in chloroform, but they were only able to obtain 4-nitro-dimethylaniline with a small amount of 3-nitiodimethylaniline. No demethylation of the N-dimethylamino group occurred. 

Similarly, from Crinum powellii, avoiding basic treatment, criwelline (241) was not obtained but the amorphous precriwelline (243) whose hydrochloride melted at 199-201° was isolated. The sequence leading from 243 to 245 and 247, the known alkaloid macronine (Vol. XI, p. 381), and its synthetic iV-demethyl derivative, respectively, established structure 243. The compound 247 was isolated from Crinum erubescens along with the carbamate 253 which probably arose from 247 during the extraction by the action of chloroform and ethanol. Epimacronine (246), another lactonic alkaloid of this series, was obtained in small amounts from 8. formosissima (50, 51). 

A new method for the demethylation of codeine to morphine, previously a capricious reaction, has been reported, the product being obtained in good yield. Demethylation by boron tribromide in chloroform gives 90—91%150 and by potassium t-butoxide in propanethiol gives 80% morphine.151 A patent describes an improved method for the preparation of codeinone from thebaine, by adding the alkaloid to anhydrous hydrogen bromide in solution in methylene chloride and dibutyl ether at -20 °C, in the presence of small quantities of iodine, followed by hydrolysis with aqueous sodium bicarbonate. The claimed yields of codeinone are 95% crude and 90% after purification.152 Codeinohe is an intermediate in the conversion of thebaine into codeine. An overall yield of 85% of codeine from thebaine, without purification of any of the intermediates, has been claimed for an... 

The N-demethylation of apomorphine, using methyl chloroformate followed by cleavage of the crude urethane with hydrazine, has been achieved.45 Normor-phothebaine, obtained by the rearrangement of northebaine, has been converted (in a series of steps) into a nitrogen mustard.46... 

Bis[4-hydroxybenzoyl] Tellurium Dichloride1 (Demethylation Method) 0.47 g (1 mmol) of bis[4-methoxybenzoyl] tellurium dichloride are dissolved in 50 ml of dry benzene and 0.4 g (3 mmol) of aluminum trichloride are added. The mixture is heated under reflux on a water bath for 30 h, then poured onto crushed icc, and allowed to warm to 20°. The resultant mixture is extracted repeatedly with chloroform, the combined extracts are dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue is recrystallized from petroleum ether. 

Substituted (e.g. /7-methyl, p-t-butyl, p-chloro, and p-amino)benzoate esters of nortropine were synthesized14 by A-demethylation of the corresponding tropanyl esters with 2,2,2-trichloroethyl chloroformate. 

Scheme 12 1 (See Ref 128 for suggested variations of the reaction sequence, and Ref. 155 for application of vinyl chloroformate to the N-demethylation step )...

In chloroform, 183 reacts with 2-methylthio-4,5,6,7-tetrahydro-l,3-benzodithiolium cation to give 184, which is demethylated by triethylamine to 185. ... 

The 17-substituent of morphinans is believed to influence its agonistic or antagonistic activity towards the opioid receptor [5]. For example, 17-methyl morphinans, morphine, and oxymorphone are agonists. On the other hand, 17-aflyl and 17-cyclopropylmethyl (CPM) morphinans, naloxone and naltrexone (1) are antagonists [5]. Therefore, a dealkylation, especially demethylation reaction of 17-substituents has been widely used to synthesize morphinan derivatives that possess various 17-substituents [27-33]. However, the reaction with chloroformates has only been applied to 14-H-morphinans. Therefore, we were interested in the 17-dealkylation reaction in 14-OH-morphinans, like naltrexone (1). In the course of the study, we found a novel reaction that cleaved the C16-N17 bond in a naltrexone derivative 35 that produced oxazolidinone 36, which lacked a D-ring (Scheme 15). 

Demethylation of methyl ethers to recover the OH group at C4 has been said to occur with trimethylsilyl iodide in chloroform (82TL197I). 

Recently Wilson and Joule 158> studied the demethylation of a variety of quaternary ammonium acetates in aprotic solvents. Earlier Lawson and Collie 92> showed that the decomposition of solid tetramethylammonium acetate at 180—200 °C gives the methyl ester in good yield. However, the use of an aprotic solvent significantly lowers the temperature (60—140 °C) required for decomposition. This reaction is most useful for the demethylation of aromatic quaternary ammonium salts that are soluble in benzene or benzene-chloroform mixtures. Its application to aliphatic quaternary ammonium salts requires a longer time, although N,N-dimethylpiperidinium acetate was demethylated at 100 °C in xylene-... 

Three new methods for the preparation of nortropine (5) have been reported.23 All three routes involve JV-demethylation by means of ethyl chloroformate, e.g. from tropine acetate (6). 

Cresylchloroformates react in a similar way as phenyl chloroformate (entry 1 to 3). The use of more electrodonating substituents like methoxy is also successfull eg for the synthesis of 4-fluoro anisole (entry 4). But, the obtained yield is modest due to demethylation of 4-fluoro anisole or of the starting material leading to tars. For electron withdrawing groups, reactivity is lower but fluoro-chloro, fluoro-bromo and difluorobenzene are prepared in high yield (entries 6 to 8). 

Substance U is a basic alkaloid, CigHgiNOs, which has been isolated from the corms (294), seeds (298), and flowers (303) of C. aiitumnale. It contains a tropolone ring and three methoxyls but no acyl group. It forms a diacetyl derivative, m.p. 226-228°, [d] —93° (chloroform), which is identical with acetyl Substance C. From the structure of Substance C, it would appear that Substance U is 3-demethyl-. -desacetylcolchicine (CXXXII). The physical properties of the free base have not been reported. 

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