467-85-6

Usage

Originator

Normethadone, Isotec, Inc.

Manufacturing Process

65 g of thin powder sodium amide was added to a solution of 289 g diphenylacetonitrile in 300 ml benzene for 15-20 minutes at temperature 45°50°C. Then the mixture was cooled to about 25°C, 182 g 2dimethyaminoethylchloride was added dropwise. On ending the reaction it was heated to reflux for 15 minutes, diluted with water, the benzene layer separated and washed with diluted hydrochloric acid. The acid layer was alkalified with sodium hydroxide, extracted with ether and dried over potash. The ether was distilled off to dryness and the residue solidified to give colorless crystals of 4-dimethylamino-2,2-diphenylbutyronitrile. The C2H5MgBr was made from 66.5 g of magnesium, 300 ml dry ether and 33 g ethyl bromide and mixed with above prepared nitrile in 150 ml toluene. After the ending of reaction, the mixture was heated for 1.5 hour on the steam bath to give hard-grained bulk. It was mixed with 600 ml concentrate hydrochloric acid in 1500 ml water. On cooling 500 ml benzene was added and three layers arose. The middle layer crystallized shortly. The crystals were filtered off, washed with 100 ml 2 N hydrochloric acid and 3 x 100 ml acetone. 6Dimethylamino-4,4-diphenyl-3-hexanone was prepared as a hydrochloride. MP: 231°C. The salt may be transformed into the base by adding of an equivalent of any basic compound (triethyl amine, soda and so on).

InChI:InChI=1/C20H25NO/c1-4-19(22)20(15-16-21(2)3,17-11-7-5-8-12-17)18-13-9-6-10-14-18/h5-14H,4,15-16H2,1-3H3

Upstream product

• 23278-88-8 4-dimethylamino-2,2-diphenyl-butyronitrile 
• 925-90-6 ethylmagnesium bromide 
• 6336-52-3 1,1-diphenylbutan-2-one 
• 107-99-3 2-(dimethylamino)ethyl chloride 
• 74-96-4 ethyl bromide 
• 86-29-3 Diphenylacetonitrile 
• 4320-42-7 3-dimethylamino-1,1-diphenyl-propan-1-ol 
• 23690-05-3 (3,3-diphenyl-allyl)-dimethyl-amine 
• 859060-20-1 (3-chloro-3,3-diphenyl-propyl)-dimethyl-amine 
• 3506-36-3 3-dimethylaminopropiophenone 
• 39186-58-8 4-bromo-2,2-diphenylbutyronitrile 

Downstream Products

• 6414-39-7 trimethyl-(4-oxo-3,3-diphenyl-hexyl)-ammonium; iodide 
• 6327-73-7 6-dimethylamino-4,4-diphenyl-hexan-3-ol 

Relevant academic research and scientific papers

Novel Dual-Target μ-Opioid Receptor and Dopamine D3Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management

The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D3R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D3R. Structure-activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.

Phenyl-substituted normethadones: Synthesis and pharmacology

Phenyl-substituted normethadone derivatives were synthesized and their affinity (IC50) for opioid receptors was determined by displacement of the specific binding sites of [3H]sufentanyl on rat brain preparations. Substitution resulted in a decrease of affinity in-vitro. These results suggest that normethadone-like compounds may interact with the P subsite of the μ-opioid receptor and that the P subsite has a well-defined cavity shape of stringent dimensions.