Synthesis of the HCV protease inhibitor Vaniprevir (MK-7009) using ring-closing metathesis strategy

A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.     

Synthesis of vaniprevir (MK-7009): lactamization to prepare a 20-membered [corrected] macrocycle

Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.     

Chemistry of bicyclic ureas. 5. Synthesis of 2,4,6,8-tetraazabicyclo[3.3.0]-3-octanone-7-thiones

Conclusions A convenient method was developed for the synthesis of 2,4,6,8-tetraazabicyclo[3.3.0]-3-octanone-7-thiones by reacting the 4,5-dihydroxy- and 4,5-dimethoxy-2-imidazolidinethiones with substituted ureas.Deceased.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1594–1597, July, 1980.     

Polycyclic aromatic hydrocarbons (PAHs) in a coal tar standard reference material—SRM 1597a updated

SRM 1597 Complex Mixture of Polycyclic Aromatic Hydrocarbons from Coal Tar, originally issued in 1987, was recently reanalyzed and reissued as SRM 1597a with 34 certified, 46 reference, and 12 information concentrations (as mass fractions) for polycyclic aromatic hydrocarbons (PAHs) and polycyclic aromatic sulfur heterocycles (PASHs) including methyl-substituted PAHs and PASHs. The certified and reference concentrations (as mass fractions) were based on results of analyses of the coal tar material using multiple analytical techniques including gas chromatography/mass spectrometry on four different stationary phases and reversed-phase liquid chromatography. SRM 1597a is currently the most extensively characterized SRM for PAHs and PASHs.     

Fischer Indole Synthesis in the Gas Phase,the Solution Phase,and at the Electrospray Droplet Interface

Previous reports have shown that reactions occurring in the microdroplets formed during electrospray ionization can, under the right conditions, exhibit significantly greater rates than the corresponding bulk solution-phase reactions. The observed acceleration under electrospray ionization could result from a solution-phase, a gas-phase, or an interfacial reaction. This study shows that a gas-phase ion/molecule (or ion/ion) reaction is not responsible for the observed rate enhancement in the particular case of the Fischer indole synthesis. The results show that the accelerated reaction proceeds in the microdroplets, and evidence is provided that an interfacial process is involved.

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Pre-treatment of HT-29 cells with 5-LOX inhibitor (MK-886) induces changes in cell cycle and increases apoptosis after photodynamic therapy with hypericin

It may be hypothesized that the lipoxygenase (LOX) metabolic pathway plays an important role in photodynamic therapy (PDT) of malignant tumours, and modification of this pathway may result in administration of lower doses of photodynamic active agents accompanied by reduced side effects. In this study, we examine in more detail the cytokinetic parameters of human colon adenocarcinoma HT-29 cells pre-treated for 48 or 24h with LOX inhibitor MK-886, followed by PDT induced by hypericin. Based on MTT assay the concentrations of both agents (MK-886 and hypericin) with relatively slight (non-significant) cytotoxic effects were selected. These concentrations were used for combined treatment, where MTT response, total cell number, floating cells quantification, viability, cell cycle progression and DNA synthesis were detected. Hoechst/PI staining, PARP fragmentation and mitochondrial membrane potential (MMP) were evaluated to determine the extent of apoptosis. While MK-886 alone caused mainly necrosis, 48h pre-treatment of cells with MK-886 followed by PDT with hypericin clearly shifted the type of cell death to apoptosis. PDT with hypericin alone caused apoptosis in 19% of the cell population. Some combined modalities significantly potentiated the apoptotic effect (31% of apoptotic cells; 2.5microM MK-886/0.1microM hypericin), i.e., by 60% more than after single treatment with hypericin. Increased apoptosis was confirmed by PARP (116kDa) cleavage to characteristic 89kDa fragments and changes in MMP. Increasing concentration of MK-886 was accompanied by massive changes in the cell cycle progression. Combined treatment with lower concentrations of MK-886 and hypericin increased accumulation of cells in the S phase, accompanied by inhibition of DNA synthesis. Increasing concentration of MK-886 in this combination caused the opposite effect, manifesting significant accumulation of cells in the G0/G1 phase. More pronounced effects were observed after the 48h pre-treatment schedule. This anti-proliferative effect was confirmed by BrdU incorporation. These results indicate that combined treatment involving PDT and LOX inhibitor MK-886 may improve the therapeutic effectiveness of PDT.     

Microfluidic reactions using [11C]carbon monoxide solutions for the synthesis of a positron emission tomography radiotracer

Microfluidic technology has been used to perform [(11)C]carbonylation reactions using solutions containing [(11)C]CO in the form of the complex, copper(i)tris(3,5-dimethylpyrazolyl)borate-[(11)C]carbonyl (Cu(Tp*)[(11)C]CO). The synthesis of the model compound [(11)C]N-benzylbenzamide and the known tracer molecule [(11)C]trans-N-[5-(2-flurophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofurane-1(3H),1'-cyclohexane]-4'-carboxamide ([(11)C]MK-0233), a ligand for the neuropeptide Y Y5 receptor, have been performed using this technique. Following semi-preparative HPLC purification and reformulation, 1262 ± 113 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 30 GBq μmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.2 ± 0.7%. Using a 3 mL vial as the reaction vessel, and following semi-preparative HPLC purification and reformulation, 1255 ± 392 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 15 GBq μmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.1 ± 2.2%.     

Synthesis of well-defined head-to-tail-type oligothiophenes by regioselective deprotonation of 3-substituted thiophenes and nickel-catalyzed cross-coupling reaction

Iterative growth of thiophene oligomers by single-step extensions has been realized by regioselective metalation of 3-substituted thiophenes with the Knochel-Hauser base (TMPMgCl·LiCl) and coupling with bromothiophene using a nickel catalyst. Treatment of 3-hexylthiophene with TMPMgCl·LiCl induces metalation at the 5-position selectively. Subsequent addition of 2-bromo-3-hexylthiophene and a nickel catalyst leads to the corresponding bithiophene. The obtained bithiophene is converted to the terthiophene and then to the quaterthiophene by repeating the similar protocol. A concise synthesis of MK-1 and MK-2, which are organic dye molecules bearing an oligothiophene moiety that are used in photovoltaic cells, has been achieved.     

Palladium-catalyzed diastereoselective synthesis of β,β-diarylpropionic acid derivatives and its application to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718

Palladium-catalyzed diastereoselective synthesis of optically active β,β-diarylpropionic acid derivatives employing 4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary under an air atmosphere in excellent yields with high diastereoselectivity is reported. The catalytic system is applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718.     

A facile synthesis of the spiroindoline-based growth hormone secretagogue,MK-677

A facile and improved route for the synthesis of the orally active spiroindoline-based growth hormone secretagogue,MK-677 was described.The key step adopted the Fischer indole/reduction strategy.The preparation of the key intermediates N-protected piperidine carboxaldehyde 5 and the N-Boc-O-benzyl-D-serine(2) are also optimized.     

CRTH2 antagonist MK-7246: a synthetic evolution from discovery through development

In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure-activity relationships (SAR) and to procure the first milligrams of diverse target molecules for in vitro evaluation. The initial aziridine opening/cyclodehydration strategy was also directly amenable to the first GMP deliveries of MK-7246 (1), streamlining the transition from milligram to kilogram-scale production needed to support early preclinical and clinical evaluation of this compound. Subsequently a more scalable and cost-effective manufacturing route to MK-7246 (1) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N-H insertion of sulfoxonium ylide 41 and conversion of ketone 32 to amine 31 in a single step with excellent enantioselectivity through a transaminase process. Reactions such as these illustrate the enabling impact and efficiency gains that innovative developments in chemo- and biocatalysis can have on the synthesis of pharmaceutically relevant target molecules.     

Stable cyclopentadienyl-type fullerenyl radical Me<Subscript>5</Subscript>C<Stack><Subscript>60</Subscript><Superscript>•</Superscript></Stack>: experimental detection by EPR spectroscopy and quantum chemical calculations

A paramagnetic compound was detected in the synthesis of a hydride (Me)₅C₆₀H with an isolated cyclopentadienyl ring. The EPR spectrum of this compound corresponds to free radical (Me)₅C₆₀• with nonequivalent Me-group protons. The structure of the radical was confirmed by quantum chemical calculations. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1597–1599, August, 2008.     

Efficient one-pot synthesis of the 2-aminocarbonylpyrrolidin-4-ylthio-containing side chain of the new broad-spectrum carbapenem antibiotic ertapenem

An efficient synthesis of the 2-aminocarbonylpyrrolidin-4-ylthio containing side chain of ertapenem (MK-0826) is described. Starting material N-(O,O-diisopropyl phosphoryl)-trans-4-hydroxy-L-proline is converted in a one-pot process to (2S)-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid monohydrochloride in 70-75% overall yield via a series of six reactions. The development of each of these reactions and the isolation of the product is discussed in detail.     

铜基甲醇合成催化剂TPR导数谱

铜基甲醇合成催化剂ＴＰＲ导数谱胡云行，万惠霖，蔡启瑞（厦门大学化学系，固体表面物理化学国家重要实验室，厦门，３６１００５）关键词ＴＰＲ，导数谱，铜基催化剂ＴＰＲ是非稳态条件下研究催化剂的有效方法。该法具有设备简单、快速和信息量大等特点，已成为常用的催...     

Electrochemical bromination of late stage intermediates and drug molecules

Aromatic CH bromination is one of the applications of late stage functionalization that provides precursors for generation of radio-labelled compounds to support drug metabolism and pharmacokinetic (DMPK) studies or provide a “handle” for further functionalization to expand SAR studies without having to resort to de novo synthesis. Electrochemical aromatic bromination was attempted on late stage intermediates and drug molecules such as cytidine, uridine, Tenofovir, MK-4618, Sch48973 and MK-8457. The reactions were conducted under mild galvanostatic electrolysis condition in aqueous NaBr solution. The brominated products were obtained and converted to the corresponding tritium labelled products. Electrochemical methodology provides an alternative way to quickly generate aryl bromides of late stage intermediates or drug molecules that are very useful in drug discovery.     

A concise synthesis of a β-lactamase inhibitor

MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N-H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.     

Inhibition of acyl coenzyme A: cholesterol acyltransferase by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

Relatively high concentrations of MK-733 (simvastatin) and MK-803 (lovastatin, mevinolin), which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, were found to inhibit acyl coenzyme A: cholesterol acyltransferase (ACAT) of rabbit intestinal microsomes with IC50's of 2.0 x 10(-5) and 3.6 x 10(-5) M, respectively. Dihydroxy acid forms of both MK-733 and MK-803 did not inhibit ACAT activity. A kinetic analysis using a Lineweaver-Burk plot indicated that MK-733 is a competitive inhibitor of ACAT, with a Ki value of 1.2 x 10(-5) M.     

On the reaction of derivatives of bis(chloromethyl)phosphonic acid with potassium iodide

Conclusions The authors have obtained derivatives of (iodomethyl)(chloromethyl)- and bis(iodomethyl)phosphonic acids by reacting derivatives of bis(chloromethyl)phosphonic acid with KI.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1597–1598, July, 1967.     

Effect of polyaniline on the stability of electrotransport characteristics and thermochemical properties of sulfocationite membranes with different polymer matrices

A comparative analysis of the electrotransport and thermochemical properties of homogeneous and heterogeneous sulfocationite membranes modified with polyaniline has been performed. The relationship between the conditions of polyaniline synthesis in the membrane matrix and their electric conductivity, electroosmotic permeability, and thermal stability was studied. The conditions of polyaniline synthesis on the surface of a heterogeneous MK-40 membrane had an insignificant effect on the amount of the introduced modifier, while the electric conductivity of the composites remained high enough. The absence of the effect of the polyaniline synthesis conditions on the electric conductivity of МK-40-based composites suggests that the heterogeneity of this membrane is a more significant factor than the polyaniline synthesis conditions. A thermogravimetric analysis of the thermochemical properties showed a significant increase in the thermal stability of the heterogeneous membrane after its modification with polyaniline. For perfluorinated membranes, the thermochemical properties changed less significantly, but the electrotransport of ions and water significantly decreased after modification.     

Determination of vitamin K homologues by high-performance liquid chromatography with on-line photoreactor and peroxyoxalate chemiluminescence detection

A sensitive and highly selective high-performance liquid chromatography (HPLC) method was developed for the determination of vitamin K homologues including phylloquinone (PK), menaquinone-4 (MK-4) and menaquinone-7 (MK-7) in human plasma using post-column peroxyoxalate chemiluminescence (PO-CL) detection following on-line ultraviolet (UV) irradiation. The method was based on ultraviolet irradiation (254 nm, 15 W) of vitamin K to produce hydrogen peroxide and a fluorescent product at the same time, which can be determined with PO-CL detection. The separation of vitamin K by HPLC was accomplished isocratically on an ODS column within 35 min. The method involves the use of 2-methyl-3-pentadecyl-1,4-naphthoquinone as an internal standard. The detection limits (signal-to-noise ratio = 3) were 32, 38 and 85 fmol for PK, MK-4 and MK-7, respectively. The recoveries of PK, MK-4 and MK-7 were greater than 82% and the inter- and intra-assay R.S.D. values were 1.9-5.4%. The sensitivity and selectivity of this method were sufficient for clinical and nutritional applications.