- Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification
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A novel, broadly applicable method for amide C-N and ester C-O bond formation is presented based on formylpyrrolidine (FPyr) as a Lewis base catalyst. Herein, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group activation, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is distinguished by excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover, high levels of functional group compatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT, yields are considerably improved (for instance from 26 to 91%) and esterification is facilitated for the first time in synthetically useful yields. These significant enhancements are rationalized by activation by means of acid chlorides instead of less electrophilic acid anhydride intermediates.
- Huy, Peter H.,Mbouhom, Christelle
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p. 7399 - 7406
(2019/08/20)
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- Efficient atom and step economic (EASE) synthesis of the "smart drug" Modafinil
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Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, MOD) is a key psychostimulant drug used for the treatment of narcolepsy and other sleep disorders that has a very low addiction liability. Recently, MOD has been clinically investigated for the treatment of cocaine addiction and used by astronauts in long-term space missions. We have developed a synthetic strategy for "smart drug" Modafinil. An efficient atom and step economic (EASE) synthesis has been carried out by the direct reaction of benzhydrol and 2-mercaptoacetamide using the recyclable heterogeneous catalyst Nafion-H along with post-sulfoxidation. This protocol exhibits improved sustainability credentials. We have also developed a superior pre-sulfoxidation approach for the synthesis of Modafinil.
- Maurya, Shivam,Yadav, Dhiraj,Pratap, Kemant,Kumar, Atul
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supporting information
p. 629 - 633
(2017/08/18)
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- HETEROCYCLIC COMPOUNDS WITH WORKING MEMORY ENHANCING ACTIVITY
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The present invention relates to a chemical compound having the general formula (I): wherein R1 and R2 are, equal or independently, aryl, heteroaryl; wherein RTA is a 2-1,3-, or 4- 1,3- or 5-1,3-thiazole ring and its use in for improving; the short term memory and/or the working memory.
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DEGENERATIVE DISORDERS AND NEUROLOGICAL DISEASES
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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 degenerative disorders and neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of narcolepsy, shift work sleep disorder, and as an adjunct treatment for obstructive sleep apnea/hypopnea, hypersomnias, like idiopathic hypersomnia, Psychiatric/neurodegenerative disorders, ADHD, Psychiatric/neurodegenerative disorders, Depersonalization disorder, Cognitive enhancement, Fatigue, Post-chemotherapy cognitive impairment and weight loss.
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- One-pot parallel synthesis of alkyl sulfides, sulfoxides, and sulfones
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A simple and cost-effective one-pot parallel synthesis approach to sulfides, sulfoxides, and sulfones from thiourea was elaborated. The method combines two procedures optimized to the parallel synthesis conditions: alkylation of thiourea with alkyl chlorides and mono or full oxidation of in situ generated sulfides with H2O2 or H2O2-(NH4)2MoO4. The experimental set up required commonly used lab equipment: conventional oven and ultrasonic bath; the work up includes filtration or extraction with chloroform. The method was evaluated on an 81 member library of drug-like sulfides, sulfoxides, and sulfones yielding the compounds on a 30-300 mg scale. A small-scale synthesis of 2-(benzhydrylsulfinyl)acetamide (modafinil) utilizing our approach resulted in similar efficiency to the published procedures.
- Bogolubsky, Andrey V.,Moroz, Yurii S.,Mykhailiuk, Pavel K.,Ostapchuk, Eugeniy N.,Rudnichenko, Alexander V.,Dmytriv, Yurii V.,Bondar, Anna N.,Zaporozhets, Olga A.,Pipko, Sergey E.,Doroschuk, Roman A.,Babichenko, Liudmyla N.,Konovets, Anzhelika I.,Tolmachev, Andrey
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p. 348 - 354
(2015/06/22)
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- Elucidation of structural elements for selectivity across monoamine transporters: Novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues
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2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (±)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (±)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (±)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT.
- Okunola-Bakare, Oluyomi M.,Cao, Jianjing,Kopajtic, Theresa,Katz, Jonathan L.,Loland, Claus J.,Shi, Lei,Newman, Amy Hauck
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p. 1000 - 1013
(2014/03/21)
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- POTENT AND SELECTIVE INHIBITORS OF MONOAMINE TRANSPORTERS; METHOD OF MAKING; AND USE THEREOF
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Disclosed herein are bisarylmethylthioacetamides and bisarylmethylthioethylamines useful as inhibitors of monoamine transporters. The compounds are potent and/or selective inhibitors of dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) reuptake via their respective transporters, DAT, SERT and NET. Also disclosed are methods for eliciting a wake-promoting or cognitive or attention enhancing effect and for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder or other neuropsychiatric disorders sleep disorders or cognitive impairment using the compounds.
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Paragraph 0076
(2014/09/29)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF NEUROLOGICAL DEGENERATIVE DISORDERS AND NEUROLOGICAL DISEASES
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Disclosed are compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. Provided are also pharmaceutical compositions comprising an effective amount of the above compounds for treating neurological degenerative disorders and neurological diseases, which may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used for the treatment of narcolepsy, shift work sleep disorder, and as an adjunct treatment for obstructive sleep apnea/hypopnea, hypersomnias, like idiopathic hypersomnia, psychiatric/neurodegenerative disorders, ADHD, psychiatric/neurodegenerative disorders, depersonalization disorder, cognitive enhancement, fatigue, post-chemotherapy cognitive impairment and weight loss.
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- Simple synthesis of modafinil derivatives and their anti-inflammatory activity
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Simple synthesis of modafinil derivatives and their biological activity are described. The key synthetic strategies involve substitution and coupling reactions. We determined the anti-inflammatory effects of modafinil derivatives in cultured BV2 cells by measuring the inhibition of nitrite production and expression of iNOS and COX-2 after LPS stimulation. It was found that for sulfide analogues introduction of aliphatic groups on the amide part (compounds 11a-d) resulted in lower anti-inflammatory activity compared with cyclic or aromatic moieties (compounds 11e-k). However, for the sulfoxide analogues, introduction of aliphatic moieties (compounds 12a-d) showed higher anti-inflammatory activity than cyclic or aromatic fragments (compounds 12e-k) in BV-2 microglia cells.
- Jung, Jae-Chul,Lee, Yeonju,Son, Jee-Young,Lim, Eunyoung,Jung, Mankil,Oh, Seikwan
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p. 10446 - 10458
(2012/11/07)
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- SARs at the monoamine transporters for a novel series of modafinil analogues
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A series of modafinil (1) analogues were synthesized wherein (1) para-halo-substitutents were added to the aryl rings, (2) the sulfoxide function was removed, and (3) the primary amide group was replaced with secondary and tertiary amides and amines to investigate the effects of these chemical modifications on dopamine transporter, serotonin transporter, and norepinephrine transporter binding. In addition, the locomotor-stimulant effects in mice of (±)-modafinil (1), its R-and S-enantiomers, and its para-chloro sulfinylacetamide analogue (5c) were compared to those of cocaine.
- Cao, Jianjing,Prisinzano, Thomas E.,Okunola, Oluyomi M.,Kopajtic, Theresa,Shook, Matthew,Katz, Jonathan L.,Newman, Amy Hauck
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supporting information; experimental part
p. 48 - 52
(2011/04/22)
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- New synthetic route to modafinil drug including desulfobenzhydrylation of sodium carbamoylmethyl thiosulfate: Experimental and quantum chemical studies
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A new synthetic route to 2-benzhydrylsulfinylacetamide (1), a nootropic drug modafinil, is described. The synthesis includes the alkylation of sodium thiosulfate with chloroacetamide to sodium carbamoylmethyl thiosulfate, the desulfobenzhydrylation of the latter by benzhydrol in formic acid to form benzhydrylthioacetamide (3a), and the further oxidation of this thioamide with hydrogen peroxide. According to B3LYP/6-31G** DFT calculations, the key step of the synthesis, namely, desulfobenzhydrylation of salt 6a, occurs only insignificantly due to the energetically unfavorable direct attack of this salt by benzhydryl formate; the reaction mainly involves the attack by the benzhydrilium carbocation Ph2CH+. The oxidation of sulfide 3a to sulfinylacetamide 1 is efficiently catalyzed by side proton-donor molecules (constituents of the transition states of the reaction). The oxidant can be the anionic form of the reactant (HO2- ion), which reacts with sulfide 3a via the unusual noncatalytic mechanism. At the step of transition state formation, this mechanism resembles the S N2 substitution.
- Bicherov,Akopova,Spiglazov,Morkovnik
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experimental part
p. 91 - 101
(2011/01/06)
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- Microbial sulfoxidation and amidation of benzhdrylsulfanyl carboxylic acids and uses thereof
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The present invention provides novel methods for the synthesis of racemic and enantiomers of modafinil via microbial oxidation-amidation transformation. The methods include the successive oxidation-amidation of benzhydrylsulfanyl carboxylic acid to produce racemic and enantiomers of modafinil using at least one microorganism of yeast, bacteria, or fungus. Also disclosed are pharmaceutical compositions of racemic and enantiomers of modafinil along with their use in the treatment of diseases, including attention deficit hyperactivity disorder and drug addiction.
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- Towards a robust and reliable method for the reduction of functionalized sulfoxides
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Several functionalized sulfoxides in the modafinil series, which bear another reducible function, were chemoselectively reduced to thioethers using the KI/AcCl system.
- Ternois, James,Guillen, Frederic,Piacenza, Guy,Rose, Sebastien,Plaquevent, Jean-Christophe,Coquerel, Gerard
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p. 614 - 617
(2013/01/03)
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- IMPROVED PROCESS FOR PREPARING BENZHYDRYLTHIOACETAMIDE
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The present invention is directed to an improved process for preparing modafinil wherein benzhydrylthioacetate is prepared in high yield and purity by the reaction of a haloacetate with the reaction product of thiourea and benzhydrol. The reaction employing the haloacetate is conducted in a solvent comprising an organic solvent such as methanol having dissolved therein an organic base or an inorganic basic salt such as sodium bicarbonate. The resulting benzhydrylthioacetate can be amidated and then oxidized to provide the pharmaceutical grade modafinil in high yield and purity.
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Page/Page column 10
(2008/06/13)
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- Microbial oxidation/amidation of benzhydrylsulfanyl acetic acid. Synthesis of (+)-modafinil
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A highly enantioselective oxidation of benzhydrylsulfanyl acetic acid to the corresponding (S)-sulfinyl carboxylic acid was achieved employing the fungus Beauveria bassiana in very good yield. This product was amidated using the bacteria Bacillus subtilis to afford (S)-modafinil in good yield.
- Olivo, Horacio F.,Osorio-Lozada, Antonio,Peeples, Tonya L.
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p. 3507 - 3511
(2007/10/03)
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- Process for the synthesis of modafinil
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The present invention relates to a process for the preparation of 2-(benzhydrylthio)acetamide (II), key intermediate for the synthesis of modafinil, by reaction of benzhydryl chloride with thiourea and chloroacetamide.
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- Synthesis and determination of the absolute configuration of the enantiomers of modafinil
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The asymmetric synthesis of both enantiomers of modafinil, a unique CNS stimulant with a reduced abuse liability, is described. This approach effectively prepares modafinil on a multigram scale in several steps from benzhydrol. The described synthetic route has also been used to produce the more water soluble analogue, adrafinil. X-ray crystallographic analysis on (-)-(diphenylmethanesulfinyl)acetic acid has determined the absolute configuration to be R.
- Prisinzano, Thomas,Podobinski, John,Tidgewell, Kevin,Luo, Min,Swenson, Dale
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p. 1053 - 1058
(2007/10/03)
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- PREPARATIONS OF A SULFINYL ACETAMIDE
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The present invention provides processes for the preparation of modafinil which includes the step of reacting benzhydrylthiol and chloroacetamide.
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- Process for the preparation of diphenylmethylthioacetamide
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The invention provides a process for the preparation of diphenylmethylthioacetamide (I) as described in Scheme 4 comprising reacting of the isothiouronium salt or its corresponding base of the formula IV with an acetamide of the formula XCH2CONH2, wherein X represents a halogen, M represents an alkali metal and A represents an anion, in a protic medium at a temperature of less than 100° C.
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