- Quantum Chemical Studies of Model Cytochrome P450 Oxidation of Amines. MNDO Pathways for Alkylamine Reactions with Singlet and Triplet Oxygen
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Reaction pathways for oxidation of ammonia and mono-,di-,and trimethylamine by singlet and triplet oxygen atoms as models for cytochrome P450 enzymatic oxidation have been characterized by using the semiempirical molecular orbital method MNDO.Enthalpies of formation have been calculated for reactants, transition states, intermediates, and produts on closed shell and triplet pathways,and free energies of reaction and activation have been calculated from them.Energy minima and transition states have been verified by calculation of force constans.The results indicate a two-step,addition-rearrangement mechanism for nonradical oxidation leading to both N-hydroxy and N-methoxy products via N-oxide intermediates.While barriers to the rearrangement are higher than to N-oxide formation,the first step is determining the overall reaction in the gas phase.On a triplet surface, both α-C- and N-oxidation are competitive.N-Oxidation via an addition mechanism appears to be favored over on H-abstractionmechanism.However, in contrast to a closed-shell mechanism, no stable N-oxide radical intermediate is found, and the barrier to formation of N-hydroxy and N-methoxyl products on a triplet surface is grater.Additional gas phase, solution, and enzymatic studies, particulary focusing on identification of transient intermediates and products, are necessary to further distinguisch among these mechanisms.
- Goldblum, Amiram,Loew, Gilda H.
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- Stereostructure Clarifying Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone B. A Highly Acid-Labile N-Protecting Group for Amides ?
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The 5S, 8′R, and 10′R configurations of militarinone B (3), which is a natural product from Paecilomyces militaris, should equal those in its biosynthetic precursor, militarinone C. The configuration at C-1′ emerged from syntheses of the militarinone B candidates 1′′S- and 1′′R-(5S,8′R,10′R)-3 from the building blocks 9, 11, 14, and 15a while introducing TMB as a more acid-labile N-protecting group for β-ketoamides than DMB. Comparisons of 1′′S- and 1′′R-(5S,8′R,10′R)-3 with natural militarinone B (3; reisolated from Nature) revealed identity versus distinctness.
- Drescher, Christian,Brückner, Reinhard
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supporting information
p. 6194 - 6199
(2021/08/18)
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- Direct Synthesis of N -Protected Serine- And Threonine-Derived Weinreb Amides via Diboronic Acid Anhydride-Catalyzed Dehydrative Amidation: Application to the Concise Synthesis of -Garner's Aldehyde
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An efficient method for the direct synthesis of Weinreb amides derived from serine and threonine derivatives via diboronic acid anhydride-catalyzed hydroxy-directed amidation is described. This is the first successful example of the synthesis of serine- or threonine-derived Weinreb amides using catalytic dehydrative amidations. The methodology could be applied to the concise synthesis of Garner's aldehyde.
- Shimada, Naoyuki,Ohse, Naoki,Takahashi, Naoya,Urata, Sari,Koshizuka, Masayoshi,Makino, Kazuishi
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supporting information
p. 1024 - 1028
(2021/05/18)
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- One-pot method for preparing O-alkyl hydroxylamine hydrochloride and N,O-dialkyl hydroxylamine hydrochloride
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The invention relates to the field of organic synthesis, in particular to a one-pot method for preparing O-alkyl hydroxylamine hydrochloride and N,O-dialkyl hydroxylamine hydrochloride. The method comprises the following steps: S1, acetylation: mixing hydroxylamine hydrochloride with water and methyl acetate, and dropwise adding a sodium hydroxide solution while stirring at room temperature to obtain an intermediate acetyl hydroxylamine; S2, alkylation: dropwise adding an alkylation reagent into the reaction kettle at normal temperature, and then heating the reactants for reaction; S3, hydrolysis and purification: after the reaction is qualified, adding concentrated sulfuric acid, performing heating hydrolysis, after the reaction is qualified, adding caustic soda flakes or liquid caustic soda to adjust the pH value to 12, carrying out atmospheric distillation and hydrochloric acid acidification, cooling the product for crystallization, and centrifuging and drying the crystal to obtaina final product. According to the invention, methyl acetate is used as an acetyl protective agent, and compared with ethyl acetate, methyl acetate has the advantages of good water solubility, small reaction steric hindrance, sufficient protection, few impurities, low price and cost and the like; therefore, the method has the advantages of high product purity, simple process operation, accessible raw materials, simple wastewater components and environment friendliness, and is suitable for industrial production.
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Paragraph 0032-0033
(2020/10/20)
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- Structure-Elucidating Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone C §
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The (polyenoyl)tetramic acid militarinone C (1) heads a family of seven members. Before our work, the configuration of C-5 was unknown whereas the configurations of C-8′ and C-10′ were either (R,R) or (S,S). We synthesized the four stereoisomers of constitution 1, which conform with these insights. This included cross-coupling both enantiomers of the western building block (8) with both enantiomers of the eastern building block (9). The specific rotations of the resulting 1 isomers suggested that natural 1 is configured like the coupling partners (S)-8 and (R,R)-9. This conclusion was corroborated by degrading natural 1 to alcohol 35 and by proving its configurational identity with synthetic (R,R)-35.
- Brückner, Reinhard,Drescher, Christian,Hamburger, Matthias,Keller, Morris,Potterat, Olivier
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supporting information
(2020/03/30)
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- Method for coproducing vasoxine hydrochloride and N,O-dimethylhydroxylamine hydrochloride
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The invention relates to the technical field of compound synthesis methods, particularly a method for coproducing vasoxine hydrochloride and N,O-dimethylhydroxylamine hydrochloride. The method comprises the following steps: carrying out methylation reaction on hydroxylamine salt under alkaline conditions by using a methylating agent to obtain a reaction solution containing vasoxine and N,O-dimethylhydroxylamine, rectifying to separate a vasoxine bottom solution and an N,O-dimethylhydroxylamine crude distillate, respectively adding hydrochloric acid for salification, concentrating and crystallizing under reduced pressure, cooling, carrying out vacuum filtration, recrystallizing with water or methanol, and drying to obtain the vasoxine hydrochloride product and N,O-dimethylhydroxylamine hydrochloride product. The method has the advantages of simple and reliable technique, high product quality, high total yield and low comprehensive cost, and is more friendly to the environment and suitable for industrial production.
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Paragraph 0042-0048
(2017/04/03)
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- Towards stapling of helical alleno-acetylene oligomers - Synthesis of an enantiopure bis(ethynylvinylidene)-substituted cyclohexadeca-1,3,9,11-tetrayne
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We are interested in developing strategies to bridge ("staple") enantiomerically pure acyclic alleno-acetylenic oligomers to enhance their conformational preferences for helical secondary structures, which are postulated to be at the origin of their exceptional chiroptical properties. We found that ring-closing metathesis (RCM), which has been used for the stapling of peptide helices, failed with an acyclic alleno-acetylene dimer decorated with lateral olefinic side chains. Instead, enyne RCM to an enantiomerically pure dienyne occurred. We switched to the introduction of diacetylene-containing bridges and report here the 15-step synthesis of a moderately strained, enantiomerically pure cyclohexa-1,3,9,11-tetrayne with an oxidative acetylenic coupling in the key step. The chiroptical properties of the new compounds are discussed. To stabilize the secondary helical structures and enhance the chiroptical properties of alleno-acetylenic oligomers by covalent linkage, two cyclization methods of enantiopure dimers (ring-closing metathesis and Hay coupling) were investigated. Olefin metathesis failed owing to concurrent enyne metathesis. Hay coupling afforded an enantiopure 16-membered macrocycle in 15 steps. Copyright
- Mueller, I.-E. Sophie,Bernet, Bruno,Dengiz, Cagatay,Schweizer, W. Bernd,Diederich, Francois
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supporting information
p. 941 - 953
(2014/03/21)
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- Towards Stapling of Helical Alleno-Acetylene Oligomers - Synthesis of an Enantiopure Bis(ethynylvinylidene)-Substituted Cyclohexadeca-1,3,9,11-tetrayne
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We are interested in developing strategies to bridge ("staple") enantiomerically pure acyclic alleno-acetylenic oligomers to enhance their conformational preferences for helical secondary structures, which are postulated to be at the origin of their exceptional chiroptical properties. We found that ring-closing metathesis (RCM), which has been used for the stapling of peptide helices, failed with an acyclic alleno-acetylene dimer decorated with lateral olefinic side chains. Instead, enyne RCM to an enantiomerically pure dienyne occurred. We switched to the introduction of diacetylene-containing bridges and report here the 15-step synthesis of a moderately strained, enantiomerically pure cyclohexa-1,3,9,11-tetrayne with an oxidative acetylenic coupling in the key step. The chiroptical properties of the new compounds are discussed. To stabilize the secondary helical structures and enhance the chiroptical properties of alleno-acetylenic oligomers by covalent linkage, two cyclization methods of enantiopure dimers (ring-closing metathesis and Hay coupling) were investigated. Olefin metathesis failed owing to concurrent enyne metathesis. Hay coupling afforded an enantiopure 16-membered macrocycle in 15 steps.
- Müller, I.-E. Sophie,Bernet, Bruno,Dengiz, Cagatay,Schweizer, W. Bernd,Diederich, Fran?ois
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supporting information
p. 941 - 953
(2015/10/05)
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- PYRIDIN-2-YL-AMINO-1,2,4-THIADIAZOLE DERIVATIVES AS GLUCOKINASE ACTIVATORS FOR THE TREATMENT OF DIABETES MELLITUS
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Provided are compounds of Formula (I): wherein R2, R3, R13, L and D2 are as defined in the specification, which are useful in the treatment and/or prevention of diseases or disorders mediated by deficient levels of glucokinase activity or which can be treated by activating glucokinase including, but not limited to, diabetes mellitus, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glycemia), as well as other diseases and disorders such as those discussed herein
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Page/Page column 127; 131
(2009/05/29)
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- DEFORMYLASE INHIBITOR, PROCESS FOR THE PREPARATION THEREOF, AND COMPOSITION COMPRISING THE SAME
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Provided are a novel compound useful for a deformylase inhibitor with excellent antibacterial activity or its pharmaceutically acceptable salt, a process for preparing the same, and an antibacterial composition including the same as an active ingredient. The deformylase inhibitor has a broad spectrum against bacteria, including bacteria with resistance to existing antibacterial agents.
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Page/Page column 10-11
(2010/11/30)
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- Reactions of Weinreb amides: formation of aldehydes by Wittig reactions
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Aldehydes are prepared in excellent yield by Wittig reactions of phosphoranes on the Weinreb amide of formic acid followed by in situ hydrolysis.
- Hisler, Kevin,Tripoli, Regis,Murphy, John A.
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p. 6293 - 6295
(2007/10/03)
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- NOVEL CONDENSED IMIDAZOLE DERIVATIVE
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Disclosed is a compound represented by the formula (1) below which has a high DPP-IV inhibitory activity and is improved in safety, toxicity and the like. Also disclosed is a prodrug of such a compound and pharmaceutically acceptable salts of them. (In the formula, R1 represents a hydrogen atom, an optionally substituted alkyl group or the like; R2 and R3 independently represent a hydrogen atom, an optionally substituted alkyl group or the like; R4 and R5 independently represent a hydrogen atom, an optionally substituted alkyl group or the like: R6 represents a hydrogen atom, an optionally substituted aryl group or the like; and -Y-NH2, represents a group represented by the following formula (A): (wherein m is 0, 1 or 2; and R7 may not exist or one or two R7 may exist and independently represent an optionally substituted alkyl group or the like) or the like.]
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Page/Page column 136-137
(2010/11/23)
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- TRICYCLIC IMIDAZOPYRIDINES
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The invention provides compounds of the formula (1), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.
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Page/Page column 68
(2010/02/14)
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- Dihydroimidazo[2,1-b]thiazole and dihydro-5h-thiazolo[3,2-A]pyrimidines as antidepressant agents
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The present invention relates to certain novel substituted dihydroimidazo[2,1-b]thiazole and dihydro-5H-thiazolo[3,2-a]pyrimidine compounds of Formula (I) including pharmaceutically acceptable salts thereof in which have affinity for 5-HT1A receptors and which inhibits neuronal reuptake of 5-hydroxytryptamine and/or noradrenaline, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage.
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- Aromatic heterocyclic derivatives as enzyme inhibitors
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The present invention discloses peptide aldehydes which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.
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Page column 44
(2010/02/04)
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- Sulfonylphenylpyrazole compounds useful as COX-2 inhibitors
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The present invention encompasses novel sulfonylphenylpyrazole compounds useful in the treatment of cyclooxygenase-2 mediated diseases.
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- Process for producing substituted amines and a method for purifying synthetic intermediates therefor
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The present invention relates to a process for producing a substituted amine represented by the general formula (IV): (wherein R2 represents a hydrogen atom, a hydrocarbon group or a heteroatom-containing hydrocarbon group, and R3 represents a hydrocarbon group or a heteroatom-containing hydrocarbon group), which comprises the steps of: (b) reacting a hydroxamic acid represented by the general formula (II): (wherein R1 represents a hydrogen atom or a hydrocarbon group) in the presence of a base with a reaction reagent capable of introducing a hydrocarbon or a heteroatom-containing hydrocarbon group to an oxygen atom and/or a nitrogen atom to form a substituted hydroxamic acid represented by the general formula (III): STR1 (wherein R1, R2 and R3 possess the same meanings as defined above), (c) hydrolyzing said substituted hydroxamic acid (III) in the presence of a base or an acid to produce a substituted amine represented by the general formula (IV): (wherein R2 and R3 possess the same meanings as defined above). The present further relates to a method for purifying a synthetic intermediate for said substituted amine.
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- Nitrosation of Amines in Nonaqueous Solvents. 3. Direct Observation of the Intermediate in Cyclohexane
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The reactions of N-methylaniline (MeAn) with 2,2-dichloroethylnitrite (DCEN) and 2,2,2-trichloroethylnitrite (TCEN) in cyclohexane, and N-methylmethoxyamine (MMA) with TCEN in the same solvent, all gave the expected N-nitrosamines. Spectrophotometric monitoring of the MeAn/DCEN and MMA/TCEN reactions showed accumulation of the reaction intermediate. These are the first nitrosations of amines by alkyl nitrites in which observation of the intermediate has been possible; this is attributed to the low basicity of these amines (a) having effectively eliminated the possibility of the intermediate decomposing by base catalysis and (b) having decreased the rate of spontaneous decomposition of the intermediate more than the rate of its formation. Because of the scant capacity of cyclohexane to stabilize charge, it is assumed that both the formation and decomposition of the intermediate occur via concerted mechanisms with four-center transition states: formation through nucleophilic attack by the amine on the nitroso group accompanied by transfer of the amine proton to this group, decomposition through simultaneous cleavage of the N-O bond, and protonation of the alkoxide leaving group.
- Boni,Garcia-Rio,Leis,Moreira
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p. 8887 - 8892
(2007/10/03)
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- Process for preparing N,O-dialkylhydroxylamine, its salts or intermediates in their synthesis
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A process for preparing N,O-dialkylhydroxycarbamic acid ester which comprises reacting hydroxylamine or its salt with dihydrocarbyl carbonate in the presence of a basic compound to prepare hydroxycarbamic acid ester and subsequently alkylating this compound with an alkylating agent; a process for recovering N,O-dialkylhydroxycarbamic acid ester which comprises azeotropically distilling the ester with water from a solution containing the ester; a process for preparing N,O-dialkylhydroxylamine which comprises hydrolyzing N,O-dialkylhydroxycarbamic acid ester in an aqueous solution or a hydrous solvent in the presence of an alkali; a process for purifying N,O-dialkylhydroxylamine hydrochloride which comprises adding aldehyde or ketone to a solution of N,O-dialkylhydroxylamine hydrochloride containing O-alkylhydroxylamine hydrochloride as impurities to convert the O-alkylhydroxylamine hydrochloride into O-alkyl aldoxime or O-alkyl ketoxime and subsequently separating the N,O-dialkylhydroxylamine hydrochloride from the reaction system; and a process for separating N,O-dialkylhydroxylamine hydrochloride which comprises (i) adding benzene or alkylated benzene to an aqueous solution containing N,O-dialkylhydroxylamine hydrochloride, azeotropically removing water or a hydrochloride solution, and, subsequently (ii)adding alcohol thereto to obtain N,O-dialkylhydroxylamine hydrochloride in the form of crystal.
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- Kinetics of the reactions of β-methoxy-α-nitrostilbene with methoxyamine and N-methylmethoxyamine. Direct observation of the intermediate in nucleophilic vinylic substitution
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A kinetic and spectroscopic study of the reactions of MeONH2 and MeONHMe with β-methoxy-α-nitrostilbene (1-OMe) in 50% Me2SO-50% water is reported. With MeONHMe, the reaction leads to the expected enamine substitution product, Ph(MeONMe)C=C(Ph)NO2 (1-MMA); with MeONH2 the product at high pH is the anion, MeON=C(Ph)C(Ph)=NO2-, while at low pH it is the imine form MeON=C(Ph)CH(Ph)NO2 rather than the enamine. At high pH and high amine concentrations, the SNV intermediates, Ph(OMe)(MeONR)CC(Ph)=NO2-, with R = H or Me, rise to detectable levels which allows their spectroscopic and kinetic characterizations. These reactions represent the first examples of a nucleophilic vinylic substitution by amine nucleophiles in which the intermediate is directly observable. Structure-reactivity comparisons between the MeONHMe reaction and the reaction of 1-OMe with piperidine and morpholine reported previously are consistent with a relatively weak dependence of the nucleophilic addition step (k1) on amine basicity (βnuc = 0.25) but a strong dependence of the leaving group expulsion step (k2) on amine pKa (βpush = 0.71); this explains why the intermediate is observable in the reaction with the relatively weakly basic MeONH2 and MeONHMe but not with more strongly basic amines. MeONH2 and MeONHMe show the enhanced reactivity expected for α-effect nucleophiles, but it is mainly reflected in an enhanced equilibrium constant for nucleophilic addition while the effect on k1 is relatively small. Steric effects are shown to play a major role in the MeONHMe reaction. One type of steric effect is caused by crowding in the intermediate which reduces the rate and equilibrium constant for intermediate formation and enhances leaving group departure. The other is steric hindrance to π-overlap in the product and the transition state leading to it which reduces the push by the nitrogen lone pair of the intermediate and hence decreases k2 for leaving group expulsion; this latter effect is stronger than the effect of crowding in the intermediate.
- Bernasconi, Claude F.,Leyes, Aquiles E.,Eventova, Irina,Rappoport, Zvi
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p. 1703 - 1711
(2007/10/02)
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- Alicyclic Nitrosamines and Nitrosamino Acids as Transnitrosating Agents
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Many alicyclic nitrosamines act as nitrosating agents under mild conditions (pH 1-3, in the presence of nucleophilic catalysts such as thiocyanate).All nitrosopiperazines, nitrosomorpholines, and nitrosamino acids tested were found to act as nitrosating agents, and certain nitrosopiperidines also showed this capability.Acyclic nitrosamines are far less reactive than functionally similar cyclic compounds.
- Singer, Sandra S.,Singer, George M.,Cole, Barbara B.
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p. 4931 - 4935
(2007/10/02)
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