70985-58-9

Upstream product

• 124-38-9 carbon dioxide 
• 16052-42-9 (1R,2S,5R)-menthyl chloride 
• 2216-51-5 (-)-menthol 
• 80482-64-0 (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxaldehyde 
• 485843-44-5 menthyl 3-carboxaldehyde 
• 16052-40-7 (-)-(1R,3R,4S)-4-isopropyl-1-methylcyclohexane-3-carboxylic acid 
• 61548-81-0 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl methanesulfonate 
• 180978-26-1 (1S,2S,5R)-1-cyano-2-isopropyl-5-methylcyclohexane 

Downstream Products

• 16052-40-7 (-)-(1R,3R,4S)-4-isopropyl-1-methylcyclohexane-3-carboxylic acid 
• 1207722-11-9 (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide 
• 1207722-22-2 (1S,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexanecarbonyl Chloride 

Relevant academic research and scientific papers

Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles

Menthyl Grignard reagent 1 from either menthyl chloride (2) or neomenthyl chloride (3) consists of menthylmagnesium chloride (1a), neomenthylmagnesium chloride (1b), trans-p-menthane (4), 2-menthene (8), 3-menthene (9), and Wurtz coupling products including symmetrical bimenthyl 13. The diastereomeric ratio 1a/1b was determined in situ by 13C NMR or after D2O quenching by 2H NMR analysis. Hydrolysis of the C-Mg bond proceeds with retention of configuration at C-1. The kinetic ratio 1a/1b from Grignard reagent generation (dr 59:41 at 50 °C in THF) is close to the thermodynamic ratio (56:44 at 50 °C in THF). Carboxylation of 1 at -78 °C separates diastereomers 1a/b to give the anion of menthanecarboxylic acid (19) from 1a, which combines with unreactive 1b to give neomenthylmagnesium menthanecarboxylate (1bI). The kinetics of epimerization for the menthyl/neomenthylmagnesium system was analyzed (ΔH? = 98.5 kJ/mol, ΔS? = -113 J/mol·K for 1bI → 1aI). Reactions of 1 with phosphorus electrophiles proceed stereoconvergently at C-1 of 1a/b to give predominantly menthyl-configured substitution products: PCl3 and 2 equiv of 1 give Men2PCl (6), which hydrolyzes to dimenthylphosphine P-oxide (7), whereas Ph2PCl with 1 equiv of 1 gave P-menthyldiphenylphosphine oxide (27) after workup in air.

Synthesis, characterization and hplc analysis of the (1S,2S,5R)-diastereomer and the enantiomer of the clinical candidate ar-15512

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.

Process for making neo-enriched p-menthane compounds

A process for making neo-enriched p-menthane intermediates is disclosed. Lewis acid-catalyzed rearrangement of an oxaspiro compound provides an aldehyde mixture comprising normal (II) and neo (III) p-menthane-3-aldehydes: with the neo aldehyde (III) as the major product. The aldehyde mixture is readily oxidized to provide the corresponding carboxylic acids, and the acids are easily converted to a host of neo-enriched p-menthane esters or amides. The esters and amides are valuable as physiological coolants.

PROCESS FOR MAKING NEO-ENRICHED p-MENTHANE COMPOUNDS

A process for making neo-enriched p-menthane intermediates is disclosed. Lewis acid-catalyzed rearrangement of an oxaspiro compound provides an aldehyde mixture comprising normal (II) and neo (III) p-menthane-3-aldehydes: with the neo aldehyde (III) as the major product. The aldehyde mixture is readily oxidized to provide the corresponding carboxylic acids, and the acids are easily converted to a host of neo-enriched p-menthane esters or amides. The esters and amides are valuable as physiological coolants.

INTERCONVERSION BETWEEN ISOMERIC P-MENTHANE-3-CARBOXYLIC ACIDS

A process for interconversion between WS-1 and neo-WS-1 by heating to a temperature in a range of from 60 degrees Celsius to 250 degrees Celsius. The heating can be done in the presence of an acid catalyst. Starting from practically pure (=98%) WS-1, or mixtures of WS-1 and neo-WS-1, practically pure (=98%) neo-WS-1 can be obtained. Starting from practically pure (=98%) neo-WS-1, or mixtures of WS-1 and neo-WS-1, practically pure (=98%) WS-1 can be obtained.