- Synthesis, characterization and hplc analysis of the (1S,2S,5R)-diastereomer and the enantiomer of the clinical candidate ar-15512
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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.
- Abás, Sònia,Escolano, Carmen,Galdeano, Carles,Pujol, Eugènia,Rodríguez-Arévalo, Sergio,Vázquez, Santiago
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- Method for preparing menthane carboxamide by taking L-menthol as raw material
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The invention relates to a method for preparing menthane carboxamide by taking L-menthol as a raw material. The menthane carboxamide is prepared through the processes of chlorination, a Grignard reaction, acidification, acylating chlorination, amidation, distillation, recrystallization and the like in sequence. The process route is mature, has the advantages of operation management simplicity andsecurity risk reduction, during a chlorination process, lower-layer waste acid water is collected and reduced pressure distillation is carried out; H2O and HCl in the acid water are removed; recoveryof ZnCl2 is realized, reduced pressure distillation completion is realized, and a reagent, namely concentrated HCl, is added into the recovered ZnCl2; a ZnCl2/HCl saturated solution is prepared again,the L-menthol is added for chlorination reaction again, the steps are repeated, the waste acid water in the chlorination reaction can be repeatedly used, the production cost is saved, the wastewatertreatment cost is reduced, and the economic benefit is improved.
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- Ester ammonolysis reaction catalyst composition and preparation method of L-menthane carboxamide
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The invention discloses an ester ammonolysis reaction catalyst composition and a preparation method of L-menthane carboxamide. The ester ammonolysis reaction catalyst comprises a catalyst and a ligand, wherein the catalyst is cuprous salt CuX, the ligand is a (R)-N, N, N, N-tetraalkyl binaphthylamine compound shown as the specification, wherein R1, R2, R3 and R4 are independently selected from thegroups shown as the specification. Menthyl chloride is used as the starting raw material in the method to react with metal magnesium to prepare menthyl magnesium chloride, then reaction with chloroformate with different substituent groups is carried out to obtain menthyl formate, and then ammonolysis under the catalysis of an ester ammonolysis catalyst composition is conducted to obtain the L-menthane carboxamide. The yield is improved, the production cost is reduced, the optical purity is high, and environmental protection and no wastewater discharge are realized.
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Paragraph 0007; 0048-0051
(2020/07/21)
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- Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles
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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.
- Koller, Sebastian,Gatzka, Julia,Wong, Kit Ming,Altmann, Philipp J.,P?thig, Alexander,Hintermann, Lukas
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p. 15009 - 15028
(2019/01/03)
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- Method for preparing menthol carboxamide intermediate peppermint acid
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The invention discloses a method for preparing a menthol carboxamide intermediate peppermint acid. The method takes L-menthol as a starting raw material and comprises the following steps: enabling theL-menthol and p-toluene sulfonyl chloride to react to obtain menthyl toluenesulfinate; then enabling the menthyl toluenesulfinate to react with sodium cyanide to obtain cyano-peppermint; finally, hydrolyzing to obtain the peppermint acid. The synthesis method disclosed by the invention is simple and is suitable for industrial production; meanwhile, a lot of difficult-to-treat wastewater is avoided. The obtained peppermint acid has a good crystal form; the purity is greater than or equal to 97 percent, the yield is greater than or equal to 85 percent and ee is greater than or equal to 99.0 percent.
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Paragraph 0031; 0032; 0038; 0039
(2018/04/03)
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- Method for preparing levorotatory menthyl formate
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The invention provides a method for preparing levorotatory menthyl formate. In the method, ether compounds are used as a reaction solvent; the temperature of a system when carbon dioxide is introduced and the introducing rate are controlled in a process of preparing the levorotatory menthyl formate, so that the levorotatory menthyl formate with high purity and high stereo-selectivity is prepared at high yield.
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Paragraph 0084; 0085; 0086; 0087; 0088; 0089; 0090-0104
(2017/03/22)
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- Ni-Catalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2
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A catalytic carboxylation of unactivated primary, secondary, and tertiary alkyl chlorides with CO2 at atmospheric pressure is described. This protocol represents the first intermolecular cross-electrophile coupling of unactivated alkyl chlorides, thus leading to new knowledge in the cross-coupling arena.
- B?rjesson, Marino,Moragas, Toni,Martin, Ruben
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supporting information
p. 7504 - 7507
(2016/07/06)
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- INTERCONVERSION BETWEEN ISOMERIC P-MENTHANE-3-CARBOXYLIC ACIDS
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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.
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Page/Page column 4
(2012/11/13)
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- Process for making neo-enriched p-menthane compounds
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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.
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Page/Page column 11-12
(2012/05/20)
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- PROCESS FOR MAKING NEO-ENRICHED p-MENTHANE COMPOUNDS
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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.
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Page/Page column 9
(2012/05/20)
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- A novel type of optically active helical polymers: Synthesis and characterization of poly(α,β-unsaturated ketone)
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New αβ-unsaturated ketone monomers, menthyl vinyl ketone (MVK), and 1-menthylbut-3-en-2-one (MBEK) were synthesized. The monomers were polymerized using butyllithium as an initiator. The polymer derived from MVK (poly-MVK) had a tremendous specific optical rotation α] 38525, which was as 32 times large as that of its monomer MVK. Poly-MVK was confirmed to keep a prevailing helicity of backbone in solution by means of comparing the specific optical rotation and the CD spectra with that of MVK and the model compound such as ethyl menthyl ketone (EMK) and n-hexyl menthyl ketone (n-HMK). This conclusion was also confirmed by the fact that the specific optical rotation and the CD signal intensity of poly-MBEK were not enough large dueto backbone flexibility caused by the effective isolation of the main chain from the bulky menthyl. The excess value of onehanded helicity of poly-MVK decreased with the increase of polymerization temperature.
- Wu, Shi,Yang, Nianfa,Yang, Liwen,Cao, Jing,Liu
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experimental part
p. 1441 - 1448
(2011/03/21)
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- N-arylsalkyl-carboxamide compositions and methods
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N-(Substituted-aryl-alkyl)-cycloalkyl carboxamide compositions are disclosed that target molecular elements on sensory nerves and on secretory epithelia. Modulation of ion fluxes in neurons and epithelia inhibits the perception of itch, pain, discomfort from the skin. By acting on these targets, preferred embodiment compositions are useful for skin and sensory disorders, and, in the case of secretory epithelia, to retard cellular proliferation. These compounds are formulated as a topical or oral preparation with prolonged duration of action.
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Page/Page column 6
(2008/06/13)
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- Compositions and methods for the treatment of disease associated with Trp-p8 expression
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Provided are small-molecule Trp-p8 modulators, including Trp-p8 agonists and Trp-p8 antagonists, and compositions comprising small-molecule Trp-p8 agonists as well as methods for identifying and characterizing novel small-molecule Trp-p8 modulators and methods for decreasing viability and/or inhibiting growth of Trp-p8 expressing cells, methods for activating Trp-p8-mediated cation influx, methods for stimulating apoptosis and/or necrosis, and related methods for the treatment of diseases, including cancers such as lung, breast, colon, and/or prostate cancers as well as other diseases, such as benign prostatic hyperplasia, that are associated with Trp-p8 expression.
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Page/Page column 21
(2008/06/13)
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- TRP-P8 ACTIVE COMPOUNDS AND THERAPEUTIC TREATMENT METHODS
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Compounds of the disclosure provide compositions, which are effective for prophylaxis and treatment of diseases or disorders, such as cell-proliferation, angiogenesis, or apoptosis mediated diseases. The disclosure encompasses compounds, analogs, prodrugs, metabolites, and pharmaceutically acceptable salts thereof, pharmaceutical compositions, and methods for prophylaxis and treatment of diseases and other maladies or conditions involving cancer, tumors, and like conditions. The disclosure also provides therapeutic methods including the administration of an effective amount of a compound of the disclosure.
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- A stereodivergent approach to chiral nonracemic N-protected α,α-dialkylated amino acids
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Menthyl carboxaldehyde is used as a chiral auxiliary to make quaternary amino acids of either configuration via a stereodivergent approach that includes an SN2′ displacement by a cuprate reagent and a Curtius rearrangement as key steps. Copyright
- Spino, Claude,Gobdout, Cedrickx
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p. 12106 - 12107
(2007/10/03)
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- Synthesis and characterisation of a suite of four chiral pyridyl alcohols derived from (-)-menthol
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Reaction of menthylmagnesium chloride with pyridine-2-carbaldehyde gives a mixture of four isomeric chiral menthyl- and neomenthyl-substituted pyridylcarbinols which were fully characterised by a combination of spectroscopic and X-ray crystallographic methods. All of these alcohols catalyse the addition of diethylzinc to benzaldehyde, but with disappointing enantioselectivities.
- Cunningham, Desmond,Gallagher, Eva T.,Grayson, David H.,McArdle, Patrick J.,Storey, Christina B.,Wilcock, Deborah J.
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p. 2692 - 2698
(2007/10/03)
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- Chiral Picket Fence Porphyrins
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The preparation of (+)-and (-)-meso-α,α,α,α-tetrakisphenyl>porphyrin as chiral picket fence porphyrins is described.The orientation of the p-menth-3-yl-carbonyl groups can be derived from proton NMR chemical shift data.Preparation procedures for the starting materials are described.
- Pfeiffer, Heinz-Peter,Sander, Hiltrud,Breitmaier, Eberhard
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p. 725 - 726
(2007/10/02)
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