Green synthesis of methadone in eutectic solvent

Eutectic solvents (DES), have attracted much attention in the last decade. With the advantages of nonflammability, thermal and chemical stability, high solubility and partial vapor pressure, non-toxicity and reasonable prices, these solvents are suggested as useful solvents. On the other hand, the eutectic solvents developed by Abbott are the new generation of ionic liquids. The mixture of eutectics is from an ammonium salt and a hydrogen bonding compound such as urea, acid, amine, and non-toxic amines. Choline chloride and urea, are quite environmentally friendly and are known practically as green solvents. The purpose of the present research is to present the synthesis of diphenyl acetonitrile with 1-dimethylamino-2-chloropropane by a eutectic’s solvent. In addition, methadone is synthesized from the reaction of 2,2-Diphenyl-4-dimethylaminovaleronitrile with ethyl magnesium bromide in the presence of solvent eutectic, which is in optimal and environmentally compatible conditions and by principles of green chemistry.

The Fukuyama Synthesis of Gelsemoxonine

The compact and highly functionalized Gelsemium alkaloids, exemplified by gelsemine (OHL20060403) and gelsemoxonine 3, offer a substantial challenge. The cytotoxicity of closely related alkaloids adds to the interest in this class. Tohru Fukuyama of the University of Tokyo envisioned (J. Am. Chem. Soc. 2011, 133, 17634) that cyclopropane-accelerated Cope rearrangement of 1 could deliver 2, ready for further functionalization to 3. The starting material for the synthesis was the enantiomerically pure acetate 4, for which a practical synthetic route was developed. Conjugate addition of 5 then proceeded away from the acetoxy group to give, after intramolecular alkylation, the cyclopropane 6. Selective protection of the derived triol 7 led to a monopivalate that was oxidized to the keto aldehyde 8. Condensation with the oxindole 9 followed by silylation then completed the assembly of 1. The trisubstituted alkene of 1 was established as a single geometric isomer. It followed that in the product 2, the oxindole and the bridging ether had the appropriate relative stereochemical arrangement. The product silyl enol ether was deprotected with fluoride to liberate the ketone 2. With 2 in hand, the next challenge was the kinetic installation of the less stable secondary aminated stereogenic center. To this end, the aldehyde 10 was exposed to TMS-CN and DBU. Under the reaction conditions, the alkene of the intermediate β,γ-unsaturated silylated cyanohydrin was brought into conjugation. Kinetic quench with allyl alcohol gave 11 with a 4:1 preference for the desired endo diastereomer 11. Inversion of the carboxyl then led to the protected amine 12. The ketone 12 was formylated under modified Vilsmeier-Haack conditions, first with Bredereck’s reagent 13 and then with oxalyl chloride, leading to the chloro aldehyde 14. The chlorine was removed by selective Pd-catalyzed reduction, and the product aldehyde was exposed to ethyl magnesium bromide followed by IBX to give the ethyl ketone 15. Epoxidation of the α,β-unsaturated ketone proceeded across the expected exo face leading to 16. The deprotected amine then opened the epoxide to establish the aminated quaternary center and complete the synthesis of gelsemoxonine 3.

Cleavage of the Methylenedioxy Ring in the Grignard Reaction of 3,4-Methylenedioxybenzonitrile

The reaction of 3,4-methylenedioxybenzonitrile (2) with ethyl magnesium bromide gives products resulting from opening of the methylenedioxy ring, namely 4-hydroxy-3-n-propoxypropiophenone (3) and 3-hydroxy-4-n-propoxypropiophenone (4) in addition to the expected product 3,4-methylenedioxypropiophenone (1). The isomeric hydroxy-n-propoxy ketones were differentiated on the basis of their spectroscopic properties.

Structural preferences for the double bond position in some unsaturated 3,3-diphenylpyrrolidines

The reaction between 3,3-diphenyl-3-cyano-1-methylpropyl isocyanate and ethyl magnesium bromide leads to 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline rather than the isomeric 2-ethylidenepyrrolidine. The protonated N-methyl analogue (identical with a major metabolite of methadone) retains the 1-pyrroline structure, but the free base is a cis-trans mixture of the corresponding 2-ethylidenepyrrolidines; the cis Me/Ph isomer preponderates and is the sole product (obtained as a quaternary salt) when the mixture is treated with methyl iodide. 5-Methyl-2-methylene-3,3-diphenylpyrrolidine, a lower homologue of the methadone metabolite, isomerizes to a 1-pyrroline derivative when protonated or methylated. All structural conclusions are based on i.r. and p.m.r. spectroscopic evidence.

Some piperazino analogues of methadone and related ketones: a novel conversion of an N-carbethoxy to a triethylmethyl group

A number of derivatives of methadone and related compounds have been prepared, where the dimethylamino group has been replaced by a 4-substituted piperazino function. The preparation of these compounds involved the reaction of N-ω-cyanoalkyl-N′-carbethoxy piperazines with ethyl magnesium bromide, and various products were obtained. These included replacement of the N′-carbethoxy group by a triethylmethyl function and cleavage of the carbethoxy group. In some cases the ω-cyano group reacted to give the corresponding ketone. Reactions of 1-benzyl-4-carbethoxy piperazine with ethyl magnesium bromide and phenyl magnesium bromide gave no evidence for the formation of the triethylmethyl group. However, cleavage of the carbethoxy group occurred and there was evidence for the formation of the corresponding amide.