96847-52-8

Usage

Uses

Intermediate in the preparation of cyclopropane derivatives.

Upstream product

• 60788-55-8 2-Hydroxymethyl-1-phenyl-cyclopropanecarbonitrile 
• 63106-93-4 1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one 
• 145193-16-4 allyl α-phenyl-α-diazoacetate 
• 140-29-4 phenylacetonitrile 
• 106-89-8 epichlorohydrin 
• 51594-55-9 (R)-(-)-epichlorohydrin 
• 67843-74-7 (S)-epichlorohydrin 
• 103-80-0 phenylacetyl chloride 
• 96847-49-3 (1S,2R)-2-(hydroxymethyl)-1-phenyl-N-[(1R)-1-phenyl-ethyl]cyclopropanecarboxamide 
• 1797-74-6 allyl phenylacetate 
• 910028-42-1 (1R,2S)-2-Hydroxymethyl-1-phenyl-cyclopropanecarbonitrile 
• 22613-99-6 cis-2-Hydroxymethyl-1-phenyl-cyclopropan-1-carbonsaeure 

Downstream Products

• 172015-99-5 (1 S,2 R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropane-carboxamide 
• 69160-63-0 (1S,2R)-2-(bromomethyl)-1-phenylcyclopropanecarboxylic acid 
• 459143-36-3 ((1S,2R)-2-Hydroxymethyl-1-phenyl-cyclopropyl)-piperidin-1-yl-methanone 
• 459143-34-1 (1S,2R)-1-phenyl-2-(hydroxymethyl)-N,N-dibenzylcyclopropanecarboxamide 
• 763126-74-5 (1R,2S)-1,2-di(hydroxymethyl)-2-phenylcyclopropane 
• 846060-60-4 (1S,2R)-2-hydroxymethyl-1-phenylcyclopropanecarboxylic acid benzyl methyl amide 
• 1237261-60-7 (1S,2R)-2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide 
• 1237261-65-2 (1S,2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide-cyclopropanecarboxamide 
• 101152-94-7 (1S,2R)-milnacipran hydrochloride 
• 172016-06-7 (1R,2S)-1-phenyl-2-(hydroxymethyl)-N,N-diethylcyclopropanecarboxamide 
• 625389-71-1 (+)-(1R,2S)-(2-hydroxymethyl-1-phenyl-cyclopropyl)-methanol 
• 1402883-27-5 2-amino-3-methyl-6-((1S,2R)-2-phenylcyclopropyl)pyrimidin-4(3H)-one 
• 96847-50-6 C₁₁H₁₂O₃ 
• 1402883-37-7 C₂₀H₂₃N₃O₅ 

Relevant academic research and scientific papers

IMPROVED PROCESS FOR THE PREPARATION OF LEVOMILNACIPRAN

The present invention discloses cost-effective, industrially efficient and safe process synthesis of levomilnacipran that is devoid of 1-phenyl-1- diethylaminocarbonyl-2- chloromethylcyclopropane.

(+)-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

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.

Preparation method of levomilnacipran hydrochloride

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.

Synthesis of enantiopure cyclopropyl esters from (-)-levoglucosenone

The biorenewable chiral synthon (-)-levoglucosenone has been converted to enantiopure cyclopropyl esters using the base-promoted carbocyclisation of 4,5-epoxyvalerates. This protocol was applied to the enantiospecific synthesis of the GABAc receptor agonist (1R,2R)-trans-2-aminomethylcyclopropanecarboxylic acid ((-)-TAMP) and its enantiomer. The process was also extended to generate 1,1,2- and 1,2,3-trisubstituted cyclopropanes resulting in a formal synthesis of the selective glutamate receptor antagonist PCCG-4.

Toward a Large-Scale Approach to Milnacipran Analogues Using Diazo Compounds in Flow Chemistry

The safe use of diazo reagents for the preparation of a key structure in the synthesis of milnacipran analogues is described herein. Using continuous flow technology, the diazo reagent is synthesized, purified, dried, and subsequently used in semi-batch mode for an intramolecular cyclopropanation. Side products formed in the reaction are isolated and rationalized to optimize the process. Different separation techniques in flow are compared with regard to their ability to produce pure and dry diazo reagents. The studies yield a scalable process to a key intermediate in the syntheses of milnacipran and its possible substituted analogues.

PROCESS FOR THE PREPARATION OF (1S,2R)-MILNACIPRAN

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).

COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS

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.

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

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).

Enantioselective iron-catalyzed intramolecular cyclopropanation reactions

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.

CYCLOPROPANE DERIVATIVE HAVING BACE1 INHIBITING ACTIVITY

The present invention relates to compounds of the Formula (I) and (II): wherein each variable is as defined in the specification, pharmaceutically acceptable salts and solvates thereof, as well as use of such compounds as a BACE1 inhibitor. The compounds of the invention are useful as an agent for treating a disease induced by production, secretion and/or deposition of amyloid β protein.