100477-72-3Relevant articles and documents
Process Research and Impurity Control Strategy of Esketamine
Gao, Shenghua,Gao, Xuezhi,Yang, Zhezhou,Zhang, Fuli
, p. 555 - 566 (2020)
An improved synthesis of (S)-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the (S)-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity. The ICH-grade quality (S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.
Enantioselective Syntheses of (S)-Ketamine and (S)-Norketamine
Chen, Cheng-Yi,Lu, Xiaowei
, p. 6575 - 6578 (2019)
An efficient asymmetric synthesis of (S)-ketamine (esketamine) based on catalytic enantioselective transfer hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future development of the drug substance. Furthermore, the route was applicable to the synthesis of (S)-norketamine via simple hydrolysis of isocyanate penultimate.
Process for (S)-Ketamine and (S)-Norketamine via Resolution Combined with Racemization
Gao, Shenghua,Gao, Xuezhi,Wu, Zenong,Li, Houyong,Yang, Zhezhou,Zhang, Fuli
, p. 8656 - 8664 (2020)
A concise, recyclable, and efficient process is presented for the preparation of (S)-ketamine (esketamine, (S)-1a) via classic resolution combined with the recycling of the undesired isomer. With commercially available ketone 2 as the starting material, this procedure features three steps including (1) an unique hydroxylation-ring expansion rearrangement, (2) mild amination via methanesulfonate, and (3) chiral separation using L-(+)-tartaric acid. The three simple steps are all performed in mild conditions and (S)-1a tartrate is obtained in 99.5percent ee without recrystallization. Subsequently, racemization of the unwanted (R)-1a remained in resolution mother liquor was performed in the presence of a Lewis acid in quantitative yield with >99.0percent chemical purity. This original and economical process afforded esketamine in 67.4percent (28.9percent without racemization) overall yield with two times recycling of the mother liquor without column purification. In addition, this procedure can also be applied to the preparation of (S)-norketamine, which is a safer potential antidepressant.
Asymmetric catalysis. Part 153: Metal-catalysed enantioselective α-ketol rearrangement
Brunner, Henri,Kagan, Henri B.,Kreutzer, Georg
, p. 2177 - 2187 (2003)
Promoted by catalytic amounts of Ni complexes tertiary α-hydroxyketones 1a, 3a-5a undergo rearrangement, forming chiral isomers 1b, 3b-5b. The best enantioselection was obtained with the model system 1-benzoylcyclopentanol 4a/2-hydroxy-2-phenylcyclohexanone 4b. In a ligand screening 2-[4-(S)-tert-butyloxazolin-2-yl]pyridine gave the highest enantiomeric excess of 46% (S)-4b. The analogous isomerisation reactions of α-hydroxyimines 6a, 7a forming chiral α-aminoketones 6b, 7b were established.
A novel strategy for the asymmetric synthesis of (S)-ketamine using (S)-tert-butanesulfinamide and 1,2-cyclohexanedione
Taghizadeh, Mohammad Javad,Gohari, Seyed Jamal Addin,Javidan, Abdollah,Moghimi, Abolghasem,Iman, Maryam
, p. 2175 - 2181 (2018)
Abstract: We present a novel asymmetric synthesis route for synthesis of (S)-ketamine?using a chiral reagent according to the strategy (Scheme 1), with good enantioselectivity (85% ee) and yield. In this procedure, the (S)-tert-butanesulfinamide (TBSA) acts as a chiral auxiliary reagent to generate (S)-ketamine. A series of new intermediates were synthesized and identified for the first time in this work (2–4). The monoketal intermediate (1) easily obtained after partial conversion of one ketone functional group of 1,2-cyclohexanedione into a ketal using ethylene glycol. The sulfinylimine (2) was obtained by condensation of (S)-tert-butanesulfinamide (TBSA) with (1), 4-dioxaspiro[4.5]decan-6-one in 90% yield. The (S)-N-tert-butanesulfinyl ketamine (3) was prepared on further reaction of sulfinylimine (2) with appropriate Grignard reagent (ArMgBr) in which generated chiral center in 85% yield and with 85% diastereoselectivity. Methylation of amine afforded the product (4). Finally, the sulfinyl- and ketal-protecting groups were removed from the compound (4) by brief treatment with stoichiometric quantities of HCl in a protic solvent gave the (S)-ketamine in near quantitative yield. Graphical abstract: [Figure not available: see fulltext.].
Copper-Assisted Direct Nitration of Cyclic Ketones with Ceric Ammonium Nitrate for the Synthesis of Tertiary α-Nitro-α-substituted Scaffolds
Zhang, Zhi-Qiang,Chen, Tao,Zhang, Fu-Min
, p. 1124 - 1127 (2017)
An efficient and direct Cu-assisted nitrating approach to create synthetically valuable and challenging tertiary α-nitro-α-substituted moieties has been developed using ceric ammonium nitrate as a nitrating reagent, oxidant, and Lewis acid. Notably, the commonly used clinical drug ketamine was smoothly synthesized in four steps.
Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions
Kassin, Victor-Emmanuel H.,Gérardy, Romaric,Toupy, Thomas,Collin, DIégo,Salvadeo, Elena,Toussaint, Fran?ois,Van Hecke, Kristof,Monbaliu, Jean-Christophe M.
, p. 2952 - 2966 (2019)
A robust three-step continuous flow procedure is presented for the efficient and sustainable preparation of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous flow processing, starts from commercially available chemicals, utilizes low toxicity reagents and a FDA class 3 solvent under intensified conditions. The procedure features a unique hydroxylation step with molecular oxygen, a fast imination relying on triisopropyl borate and a thermolysis employing Montmorillonite K10 as a heterogeneous catalyst, all three steps being performed in ethanol. The three individual steps can be run independently or can be concatenated, thus providing a compact yet efficient setup for the production of ketamine. The scalability of the critical hydroxylation step was assessed in a commercial pilot continuous flow reactor. The process can also be adapted for the preparation of ketamine analogs. A thorough computational study on the backbone rearrangement of the cyclopentylphenylketone scaffold under thermal stress rationalizes the experimental selectivity and the various experimental observations reported herein.
LONG-ACTING INJECTABLE FORMULATIONS OF KETAMINE PAMOATE SALTS
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Page/Page column 12; 13, (2021/06/26)
Provided are sustained-release pharmaceutical compositions including a ketamine pamoate salt and a pharmaceutically acceptable carrier thereof. The compositions include aqueous suspension, solution and matrix delivery system, which can provide sustained release for anesthesia, analgesia or treatment of central nervous system and anti-inflammatory diseases.
Cycloalkyl-Diamines for the Treatment of Pain
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Paragraph 0175-0180, (2021/02/26)
The invention is directed to a method of treatment for pain, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
Racemization method of ketamine and derivative or salt thereof
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Paragraph 0113; 0114, (2021/02/20)
The invention discloses a racemization method of ketamine and a derivative or salt thereof. The racemization method comprises the following step: in a solvent, under the action of a catalyst and at the reaction temperature of 110-200 DEG C, carrying out a
