63106-93-4Relevant academic research and scientific papers
Microbiological transformations 34: Enantioselective hydrolysis of a key-lactone involved in the synthesis of the antidepressant milnacipran
Viazzo, Pascale,Alphand, Veronique,Furstoss, Roland
, p. 4519 - 4522 (1996)
The enantioselective hydrolysis of a key-lactone allowing for the synthesis of the antidepressant milnacipran is described. Several biocatalysts were screened in order to achieve this biotransformation, the best results being obtained using whole-cells cultures of the fungi Beauveria sulfurescens and Cunninghamella blakesleeana.
Tandem Insertion/[3,3]-Sigmatropic Rearrangement Involving the Formation of Silyl Ketene Acetals by Insertion of Rhodium Carbenes into S-Si Bonds
Combs, Jason R.,Lai, Yin-Chu,Van Vranken, David L.
, p. 2841 - 2845 (2021/05/05)
Allyl 2-diazo-2-phenylacetates are shown to react with trimethylsilyl thioethers in the presence of rhodium(II) catalysts to generate α-allyl-α-thio silyl esters. The transformation involves a tandem process involving formal rhodium-catalyzed insertion of the carbene group into the S-Si bond to generate a silyl ketene acetal, followed by a spontaneous Ireland-Claisen rearrangement. The silyl ester products were isolated as the corresponding carboxylic acids after aqueous workup. Intramolecular cyclopropanation of the allyl fragment generally competes with addition of the heteroatom to the carbene center. The reaction occurs under mild conditions and in high yield, allowing for rapid entry into rearrangement tetrasubstituted products. Propargyl esters were shown to generate the corresponding α-allenyl products.
Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation
Clemenceau, Antonin,Thesmar, Pierre,Gicquel, Maxime,Le Flohic, Alexandre,Baudoin, Olivier
, p. 15355 - 15361 (2020/10/20)
Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.
IMPROVED PROCESS FOR THE PREPARATION OF LEVOMILNACIPRAN
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Page/Page column 7-8, (2019/06/09)
The present invention discloses cost-effective, industrially efficient and safe process synthesis of levomilnacipran that is devoid of 1-phenyl-1- diethylaminocarbonyl-2- chloromethylcyclopropane.
Preparation method of levomilnacipran hydrochloride
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Paragraph 0057-0058, (2018/09/28)
The invention relates to the field of chemical medicines and organic synthesis and in particular relates to a preparation method of levomilnacipran hydrochloride. Aiming at solving the problems of anexisting method for preparing the levomilnacipran hydrochloride that the cost is relatively high or a generation process is relatively dangerous so that large-scale industrial production is limited, the preparation method is characterized by comprising the following steps: [1] enabling phenylacetonitrile and (R)-2-chloromethyl ethylene oxide to react under the action of sodium amide to obtain a compound 1; then carrying out hydrolysis cyclization on the compound 1 to obtain a compound 2; [2] enabling the compound 2 and thionyl chloride to react in alcohol, so as to obtain a compound 3; [3] enabling the compound 3 to be subjected to exchange reaction through introducing nitryl and amino, so as to obtain a compound 6; [4] reducing nitryl in the compound 6 and forming salt in situ to obtain the levomilnacipran hydrochloride. The preparation method provided by the invention is applicable to industrial production of the levomilnacipran hydrochloride.
(+)-Methyl (1 R, 2S)-2-{[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate [(+)-MR200] derivatives as potent and selective sigma receptor ligands: Stereochemistry and pharmacological properties
Amata, Emanuele,Rescifina, Antonio,Prezzavento, Orazio,Arena, Emanuela,Dichiara, Maria,Pittalà, Valeria,Montilla-García, ángeles,Punzo, Francesco,Merino, Pedro,Cobos, Enrique J.,Marrazzo, Agostino
supporting information, p. 372 - 384 (2018/01/17)
Methoxycarbonyl-1-phenyl-2-cyclopropylmethyl based derivatives cis-(+)-1a [cis-(+)-MR200], cis-(-)-1a [cis-(-)-MR201], and trans-(±)-1a [trans-(±)-MR204], have been identified as new potent sigma (σ) receptor ligands. In the present paper, novel enantiomerically pure analogues were synthesized and optimized for their σ receptor affinity and selectivity. Docking studies rationalized the results obtained in the radioligand binding assay. Absolute stereochemistry was unequivocally established by X-ray analysis of precursor trans-(+)-5a as camphorsulfonyl derivative 9. The most promising compound, trans-(+)-1d, showed remarkable selectivity over a panel of more than 15 receptors as well as good chemical and enzymatic stability in human plasma. An in vivo evaluation evidenced that trans-(+)-1d, in contrast to trans-(-)-1d, cis-(+)-1d, or cis-(-)-1d, which behave as σ1 antagonists, exhibited a σ1 agonist profile. These data clearly demonstrated that compound trans-(+)-1d, due to its σ1 agonist activity and favorable receptor selectivity and stability, provided an useful tool for the study of σ1 receptors.
PROCESS FOR THE PREPARATION OF (1S,2R)-MILNACIPRAN
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Page/Page column 10; 11, (2016/06/01)
The invention relates to a process for the preparation of Levomilnacipran, a compound useful in the treatment of depression, comprising the following steps: a) directly converting the enantiomerically enriched form of alcohol (D) into the enantiomerically enriched form of the phthalimido derivative (C) by treatment with phthalimide in the presence of a trialkyl or triarylphosphine and of a dialkyl azodicarboxylate, formula (I) wherein the amount of phthalimide is comprised between 1 and 1.3 equivalents with respect to the molar amount of alcohol (D) used, and the amounts of both the phosphine and the azodicarboxylate are comprised, independently from each other, between 1 and 1.5 equivalents with respect to the molar amount of alcohol (D) used; b) deblocking the enantiomerically enriched form of the phthalimido derivative (C) to obtain Levomilnacipran, formula (II).
Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist
Yoshida, Yu,Naoe, Yoshimitsu,Terauchi, Taro,Ozaki, Fumihiro,Doko, Takashi,Takemura, Ayumi,Tanaka, Toshiaki,Sorimachi, Keiichi,Beuckmann, Carsten T.,Suzuki, Michiyuki,Ueno, Takashi,Ozaki, Shunsuke,Yonaga, Masahiro
supporting information, p. 4648 - 4664 (2015/06/30)
The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements. (Chemical Equation Presented).
COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
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Paragraph 0122; 0123, (2015/05/05)
The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of neurological conditions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of fibromyalgia, depression, neuropathic pain, severe pain, chronic pain, generalized pain, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.
Enantioselective iron-catalyzed intramolecular cyclopropanation reactions
Shen, Jun-Jie,Zhu, Shou-Fei,Cai, Yan,Xu, Huan,Xie, Xiu-Lan,Zhou, Qi-Lin
supporting information, p. 13188 - 13191 (2015/01/09)
An iron-catalyzed asymmetric intramolecular cyclopropanation was realized in high yields and excellent enantioselectivity (up to 97% ee) by using the iron complexes of chiral spiro-bisoxazoline ligands as catalysts. The superiority of iron catalysts exhibited in this reaction demonstrated the potential abilities of this sustainable metal in asymmetric carbenoid transformation reactions.
