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Interaction type of modafinil with calf thymus DNA (ct-DNA) was examined systematically using ethidium bromide (EB) as a fluorescence probe by fluorescence spectroscopy, UV–Vis spectroscopy, viscosity and molecular docking method. The fluorescence quenchi

A nickel-catalyzed oxidative dehydrogenative coupling reaction of alkane with thiol for the construction of C(sp3)-S bond has been established, affording more than 50 alkyl thioethers. Notably, pharmaceutical and agrochemicals, such as Provigil, Chlorbenside and Pyridaben, were readily synthesized by this approach. The sterically hindered ligand BC and disulfide which was formed in situ oxidation of thiol, efficiently avoiding nickel-catalyst poisoning. A set of mechanistic experiments disclose both Ni-catalyzed and Ni-free HAA processes.

Photoactive two-dimensional covalent organic frameworks (2D-COFs) have become promising heterogenous photocatalysts in visible-light-driven organic transformations. Herein, a visible-light-driven selective aerobic oxidation of various small organic molecules by using 2D-COFs as the photocatalyst was developed. In this protocol, due to the remarkable photocatalytic capability of hydrazone-based 2D-COF-1 on molecular oxygen activation, a wide range of amides, quinolones, heterocyclic compounds, and sulfoxides were obtained with high efficiency and excellent functional group tolerance under very mild reaction conditions. Furthermore, benefiting from the inherent advantage of heterogenous photocatalysis, prominent sustainability and easy photocatalyst recyclability, a drug molecule (modafinil) and an oxidized mustard gas simulant (2-chloroethyl ethyl sulfoxide) were selectively and easily obtained in scale-up reactions. Mechanistic investigations were conducted using radical quenching experiments and in situ ESR spectroscopy, all corroborating the proposed role of 2D-COF-1 in photocatalytic cycle.

New 1,2-azolylamidino complexes cis-[Ru(bipy)2(NH=C(R)az*-κ2N,N)](OTf)2 (R = Me, Ph; az? = pz, indz, dmpz) are synthesized via chloride abstraction after a subsequent base-catalyzed coupling of a nitrile with the previously coordinated 1,2-azole. The synt

Inspired by biological flavin catalysis, the nonionic alloxan derivatives were applied as the biomimetic catalysts for various oxidations, catalyzing oxidations of sulfides and amines with hydrogen peroxide or molecular oxygen under mild conditions with high yields in a short time. The whole catalytic cycle has been verified to be a biomimetic approach through the formation of the alloxan hydroperoxide reactive intermediate. Additionally, encouraging asymmetric catalytic results have been obtained with an easily prepared chiral alloxan in a sulfoxidation reaction.

Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late-stage oxygenation of sulfur-containing complex molecules with ground-state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+) enabled the efficient synthesis of sulfones. The ligand-to-metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late-stage oxygenation in an atom- and step-efficient manner.

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.

The invention relates to a preparation method of alkyl sulfide. The method comprises the following steps: under the protection of nitrogen, sequentially adding transition metal, a nitrogen ligand, a cocatalyst, an oxidant, a solvent, alkane and thiophenol or mercaptan into a reaction tube, carrying out oxidative dehydrogenation coupling reaction at 80-150 DEG C, ending the reaction after 6-48 hours, evaporating the solvent to dryness, and carrying out column chromatography separation to obtain the alkyl sulfide compound. The method is simple in synthesis process, mild in reaction condition, high in yield and easy to industrialize.

The invention discloses a method for selectively synthesizing a sulfoxide compound shown as a formula (II) and a sulfone compound shown as a formula (III). In a reaction solvent, thioether (I) is usedas a reaction raw material and oxygen as an oxidation reagent, under the catalytic action of visible light and a photosensitive reagent; under the assistance of an additive, when a large-polarity proton-containing additive such as an acid and an alcohol or a solvent or an additive with excellent electron donating ability is used, a sulfoxide compound (II) is selectively generated; and when a small-polarity aprotic additive or a solvent is used, a sulfone compound (III) is selectively generated. The synthesis method has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and excellent functional group tolerance. According to the invention, synthesis and modification of some medicines are realized, and an efficient method for selectively constructing sulfoxide and sulfone compounds is provided for medicinal chemistry research.

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.

Metal- and additive-free oxidation of a series of sulfides/thioketones has been achieved using cyclic diacyl peroxides as mild oxygen sources. This protocol features simple manipulation, high chemo- and diastereoselectivity, and a broad substrate scope (up to 42 examples), tolerates many common functional groups, and is scalable and applicable to the late-stage sulfoxidation strategy. A preliminary mechanistic study by quantum mechanical calculations suggests that a single two-electron transfer process is energetically more favorable, and indicates the reactivity of cyclic diacyl peroxides distinct from conventional acyclic acyl peroxides.

We have developed a metal-free process for the aerobic photooxygenation of sulfides to sulfoxides mediated by riboflavin tetraacetate or riboflavin (vitamin B2) photocatalysts and visible light (450 nm) in an acetonitrile-water (85:15 v/v) mixture. The optimised solvent system leads to both singlet-oxygen and electron-transfer pathways in photooxygenation, thus allowing oxidation of electron-poor and electron-rich thioanisoles, dialkyl sulfides and sterically hindered sulfides. Besides having a broad substrate scope, the method has very short reaction times and requires low catalyst loading (down to 0.1 mol%). These properties are due to the high photocatalyst stability and the extremely high quantum yields (1.3 for thioanisole oxygenation). Moreover, the method is chemoselective, producing only sulfoxides without overoxidation to sulfones. Taking into account the broad substrate scope, high selectivity and high efficiency, this method distinguishes itself from those previously reported. Other advantages include easy work-up of the reaction mixture, the availability and biodegradability of the photocatalysts and mild reaction conditions. We demonstrated, on a preparative scale, its practical application in the synthesis of the psychostimulant modafinil, in the selective oxidation of methionine derivatives, and in the detoxification of mustard gas. (Figure presented.).

VO2(picolinichydrazone) complex as a catalyst was stabilized on a SBA-15 mesoporous silica as a catalytic support by using (3-chloropropyl)triethoxysilane as a connector. SBA-15 is nanoporous and has a high ratio of surface area to volume. The immobilization of a metal–Schiff base complex to the surface area of SBA-15 can improve its catalytic effects by increasing the catalytic surface area. Unlike homogeneous catalysts, heterogeneous catalysts can be recovered and reused several times without any significant loss of catalytic activity. A vanadium–Schiff base complex-functionalized SBA-15 was synthesized by covalency connected by a pre-synthesised VO2(picolinichydrazone) complex to silanated SBA-15. The synthesized vanadium–Schiff base complex was characterized by proton nuclear magnetic resonance (1H NMR) spectroscopy, carbon nuclear magnetic resonance (13C NMR) spectroscopy and Fourier transform infrared spectroscopy (FT-IR), and the final V/SBA-15 was characterized by FT-IR, ultraviolet–visible spectrophotometry and X-ray powder diffraction. The morphology of V/SBA-15 was also obtained by scanning electron microscopy and transmission electron microscopy. The catalytic effect was examined by using V/SBA-15 as a heterogeneous catalyst in sulfoxidation reactions. The synthesis of modafinil and modafinic acid by pharmaceutical sulfoxidation of solfides was carried out and the effects of different solvents, reaction times and also recoverability and reusability of the heterogeneous catalyst were investigated. This catalyst showed high yield of sulfide conversion, stability and recyclability in the sulfoxidation of sulfides.

A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of substituent and is remarkable for derivatives with an electron-withdrawing group, showing reactivity comparable to that of flavinium salts which are the prominent organocatalysts for oxygenations. Because of their high stability and good accessibility, 4-(trifluoromethyl)pyrimidinium and 3,5-dinitropyridinium triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their ability to readily form adducts with nucleophiles, as documented by low pKR+ values (pKR+ red > -0.5 V). Hydrogen peroxide adducts formed in situ during catalytic oxidation act as substrate oxidizing agents. The Gibbs free energies of oxygen transfer from these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-311++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing agents in monooxygenases.

Amphiphilic pyridinium and diazinium salts were shown to be effective catalysts in two-phase (water/chloroform or water/dichloromethane) sulfoxidations and N-oxidations with hydrogen peroxide under mild conditions. This unprecedented oxidation method utilizes covalent bonding of hydrogen peroxide to a simple pyridinium or diazinium nucleus to increase the lipophilicity of the hydroperoxide species and to subsequently activate it for oxidations in a non-polar medium. The catalytic efficiency was found to depend on the type of heteroarenium core and on the lipophilicity of the catalyst. Five series of heteroarenium catalysts were prepared and investigated: 1-Alkyl-3,5-dicyanopyridinium, 1-alkyl-3,5-dinitropyridinium, 1-alkyl-3-cyanopyrazinium, 1-alkyl-4-cyanopyrimidinium and 1-alkyl-4-(trifluoromethyl)pyrimidinium triflates (alkyl=butyl, hexyl, octyl, decyl, dodecyl and hexadecyl). Among them, the 1-octyl-3,5-dinitropyridinium and 1-decyl-4-(trifluoromethyl)pyrimidinium triflates were found to be superior catalysts, showing the best stability and the highest catalytic activity, achieving acceleration by a factor of 350 relative to the non-catalyzed reaction. In contrast to other organocatalytic two-phase oxidations that use hydrogen peroxide, the presented method is characterized by high chemoselectivity and low catalyst loading (5mol%) and with the reactions being performed under mild conditions, that is, at 25 C using diluted hydrogen peroxide and a non-basic aqueous phase. The catalysts have simple structures and are readily available from commercial materials. Practical applications are demonstrated via the oxidation of several types of sulfides and amines.

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.

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.

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.

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.

A series of 3-substituted pyrazinium tetrafluoroborates was prepared as simple analogues of flavinium salts which are efficient organocatalysts for oxidations with hydrogen peroxide. It was shown that pyrazinium derivatives with an electron-withdrawing su

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.

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.

The present invention generally relates to an improved process for preparing modafinil and analogs thereof. The process minimizes impurities and improves the overall yield by oxidizing a modafinil intermediate compound in a reaction mixture including an a

The invention encompasses processes for preparing intermediates, such as R-modafinic acid or (R)-C1-2 alkyl ester, of modafinic acid, and the conversion of the intermediates to armodafinil.

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.

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.

The present invention provides processes for the preparation of modafinil which includes the step of reacting benzhydrylthiol and chloroacetamide.

The invention relates to a process for preparing modafinil having a defined granulometry which comprises the steps of:a) preparing a solution of DMSAM ;b) contacting the solution obtained with NH3 at a predetermined temperature and a predetermi

A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.

A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.

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.

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.

A process for the preparation of 2-[(diphenylmethyl)sulfinyl]acetamide (I) comprising the oxidation of sodium 2-[(diphenylmethyl)sulfenyl]acetate to the corresponding sulfoxide and the derivatization of the latter to amide.

The present invention provides processes for the preparation of modafinil which includes the step of reacting benzhydrylthiol and chloroacetamide.

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.

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.

Mixtures of a modafinil compound with a cyclodextrin, methods for their use, and compositions thereof are disclosed, along with complexes comprising a modafinil compound and a cyclodextrin which are taste-masked and suitable for oral consumption in an aqueous solution.

Novel acetamide derivatives have been discovered to have useful pharmaceutical activity on the central nervous system. They may be prepared by reacting the corresponding ester or acid halide with the appropriately substituted amine.