- Reactions of 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide in Various pH Solutions
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Diazepam (1) is a frequently prescribed hypnotic/anxiolytic drug worldwide. 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide (2) is an initial alkaline hydrolysis product of 1. The mechanisms in the conversion of 2 to 2-methylamino-5-chloro-α-(phenylbenzylidene)glycinate (3), 2-methylamino-5-chlorobenzophenone (4), and 1 in aqueous solutions with pH ranging from 0 to 12.2 is the subject of this report. Results of temperature-dependent hydrolysis kinetics and product identification indicated that: (1) in solutions with pH between 7 and 12.2, 2 underwent a ring-opening reaction to form 3; the rate decreased with increasing pH. (2) In solutions with pH between 2 and 7, 2 was rapidly converted to 3, followed by a pH-dependent conversion to 4; the rate increased with decreasing pH and became less sentitive to pH at pH ≤ 4.5. (3) In solutions with pH between 0 and 2, 2 was rapidly converted to 4 and 1; the percentage of 1 increased with decreasing pH. (4) A 2 containing one oxygen-18 atom lost 50% of its oxygen-18 following conversion to 1 in 1 M HCl. In addition to understanding the mechanism in the transformations of 2 in various pH solutions, this study established a simple and efficient method in the quantitative conversion of 1 to 4 and in the preparation of an oxygen-18-containing 1 at C2 position.
- Yang, Shen K.
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- 2-methylamino-5-chlorobenzophenone
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Intramolecular hydrogen bonding is present in 2-methylamino-5-chlorophenyl phenyl ketone, C14H12ClNO, and the phenyl rings are inclined by 54.39 (8)° with respect to one another. The Cl...Cl intermolecular separation of 3.355 (2) A is considerably less than the sum of the van der Waals radii.
- Cox, Philip J.,Anisuzzaman, Abu T. Md.,Skellern, Graham G.,Pryce-Jones, R. Howard,Florence, Alastair J.,Shankland, Norman
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- Phase transfer catalysed N-monoalkylation of amino anthraquinones
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1-Alkylaminoanthraquinones (2a-f) and 1,4-bisalkylaminoanthraquinones (4a-c) were prepared from aminoanthraquinones (1,3) by alkylation with alkyl sulphate/alkyl halide in presence of powdered sodium hydroxide, potassium carbonate and phase transfer catalyst.
- Ramrao,Ramkumar,Anant,Ramanuja
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- High-performance liquid chromatographic method for assay of otilonium bromide, diazepam, and related compounds in finished pharmaceutical forms
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A rapid, simple, stability-indicating assay procedure for otilonium bromide, a smooth muscle relaxant agent, and diazepam in composite tablet analysis was developed with high-performance liquid chromatography. The tablet matrix was dissolved with water, and drugs were extracted with acetonitrile containing an internal standard. An aliquot was centrifuged and chromatographed on a 5-μm, reversed-phase column with 0.5 M sodium acetate trihydrate buffer containing 5 mM 1-heptanesulfonic acid monohydrate sodium salt:methanol (30:70; v/v; adjusted to pH 6.0 with glacial acetic acid) as the mobile phase. The selectivity of the chromatographic system was demonstrated by resolving both compounds from various potential degradation products of each compound. The method is linear, quantitative, and reproducible.
- Mannucci,Bertini,Cocchini,Perico,Salvagnini,Triolo
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- Mechanism of Alkaline Hydrolysis of Diazepam
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Diazepam (1) is a frequently prescribed hypnotic/anxiolytic drug in worldwide use. Compound 1 is hydrolyzed in alkaline medium to form 2-methylamino-5-chlorobenzophenone imine (2) and 2-methylamino-5-chlorobenzophenone (3); the ratio of 2:3 increases with increasing NaOH concentration (J. Pharm. Sci. 85, 745-748, 1996). The mechanism in the conversion of 1 to 2 and 3 via various intermediates is the subject of this report. Results of hydrolysis kinetics and structural identification of some intermediate products indicated an initial hydroxide attack at the C2-carbonyl carbon of 1, resulting in the formation of a dioxide (7, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide). Compound 7 was characterized by proton NMR spectroscopy and via its monomethyl ether (8, 7-chloro-1,3-dihydro-2-hydroxy-2-methoxy-1-methyl-5-phenyl-2H-1,4-benzodiazepme) . The seven-member diazepine ring of 7 opened at the N1-C2 bond to form aglycinate [5, 2-methylamino-5-chloro-α-(phenylbenzylidene)glycinate]. Compound 7 (and/or 5) underwent an additional hydroxide attack at the C5-N4 imine bond to form a tetrahedral intermediate, which decomposed to form 2 and 3.
- Yang, Shen K.
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- Hydrolysis of temazepam in simulated gastric fluid and its pharmacological consequence
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Temazepam (TMZ), a hypnotic and anxiolytic drug, underwent hydrolysis in simulated gastric fluid (SGF; pH 1.2). The hydrolysis reaction of TMZ in acetonitrile:SGF (1:19, v/v) at 37 °C was an apparent first-order reaction, with a half-life of 5.47 ± 0.17 h (i.e., ~12% of the remaining TMZ was hydrolyzed per hour). The predominant hydrolysis product (2'-benzoyl-4'- chloro-N-methyl-2-amino-2-hydroxyacetanilide) and a minor hydrolysis product [2-(methylamino)-5-chlorobenzophenone], derived from acid-catalyzed reaction of TMZ in an aqueous solution, were characterized by ultraviolet-visible absorption mass, infrared, and proton nuclear magnetic resonance spectra analyses. The kinetics of the hydrolysis reaction were studied as a function of acid concentration, temperature, and ionic strength and in deuterated solvent. Results indicated that the predominant hydrolysis reaction at pH ? pK(a) (1.46) was caused by protonation at N4, followed by a nucleophilic attack by water at C5 of the C5-N4 iminium ion and a subsequent ring-opening reaction. Pharmacological activity tests in mice indicated that the predominant hydrolysis product of TMZ was inactive. The results suggest that a fraction of an orally taken TMZ may be inactivated by hydrolysis in the highly acidic gastric fluid.
- Tian Jian Yang,Quan Long Pu,Yang
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- Kinetics of the acid hydrolysis of diazepam, bromazepam, and flunitrazepam in aqueous and micellar systems
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A kinetic study of the acid hydrolysis of aqueous diazepam, bromazepam, and flunitrazepam was carried out at 25 °C using a spectrophotometric method. For diazepam and flunitrazepam, the experimental pseudo first-order rate constant decreased as the acid concentration was increased. The contrary behavior was found in the case of bromazepam. A kinetic scheme that includes the hydrolysis reaction of both protonated and nonprotonated species of the drug can account for these results. Also, the kinetics of the acid hydrolysis of the same drugs in the presence of micellar aggregates [nonionic polyoxyethylene-23-dodecanol (Brij 35); cationic cetyl trymethyl ammonium bromide (CTAB); and anionic sodium decyl (SdeS), dodecyl (SDS), and tetradecyl (STS) sulfate] was studied at 25 °C. Negligible effects were observed in the cases of nonionic and cationic micelles. Anionic micelles produced an inhibitory effect in the reaction velocity. This effect increased as the hydrophobic nature of the surfactant increased. All these facts are interpreted quantitatively by means of a pseudophase model.
- Moro,Novillo-Fertrell,Velazquez,Rodriguez
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- Ru-Catalyzed Selective Catalytic Methylation and Methylenation Reaction Employing Methanol as the C1 Source
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Methanol can be employed as a green and sustainable methylating agent to form C-C and C-N bonds via borrowing hydrogen (BH) methodology. Herein we explored the activity of the acridine-derived SNS-Ru pincer for the activation of methanol to apply it as a C1 building block in different reactions. Our catalytic system shows great success toward the β-C(sp3)-methylation reaction of 2-phenylethanols to provide good to excellent yields of the methylated products. We investigated the mechanistic details, kinetic progress, and temperature-dependent product distribution, which revealed the slow and steady generation of in situ formed aldehyde, is the key factor to get the higher yield of the β-methylated product. To establish the environmental benefit of this reaction, green chemistry metrics are calculated. Furthermore, dimerization of 2-naphthol via methylene linkage and formation of N-methylation of amine are also described in this study, which offers a wide range of substrate scope with a good to excellent yield.
- Biswas, Nandita,Srimani, Dipankar
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p. 10544 - 10554
(2021/07/31)
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- Cobalt-Catalyzed Electrophilic Aminations with Anthranils: An Expedient Route to Condensed Quinolines
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The reaction of various organozinc pivalates with anthranils provides anilines derivatives, which cyclize under acidic conditions providing condensed quinolines. Using alkenylzinc pivalates, electron-rich arylzinc pivalates or heterocyclic zinc pivalates produces directly the condensed quinolines of which several structures belong to new heterocyclic scaffolds. These N-heterocycles are of particular interest for organic light emitting diodes with their high photoluminescence quantum yields and long exciton lifetimes as well as for hole-transporting materials in methylammonium lead iodide perovskites solar cells due to an optimal band alignment for holes and a large bandgap.
- Li, Jie,Tan, Eric,Keller, Niklas,Chen, Yi-Hung,Zehetmaier, Peter M.,Jakowetz, Andreas C.,Bein, Thomas,Knochel, Paul
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supporting information
p. 98 - 103
(2019/01/08)
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- Synthesis method of 2-methylamino-5-chlorobenzophenone
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The invention discloses a synthesis method of 2-methylamino-5-chlorobenzophenone. The method includes the steps of: subjecting an aqueous solution of N-methyl-3-phenyl-5-chloro-2, 1-benzisoxazole methyl quaternary ammonium salt (II) and a hydrazine hydrate aqueous solution to reduction reaction under the catalysis of zinc chloride to obtain 2-methylamino-5-chlorobenzophenone (1). Compared with theexisting synthesis methods, the method provided by the invention has the advantages of simple synthesis method, high catalytic activity, easy separation and purification of product, high product purity, high yield, low emission of three wastes, small environmental pollution and the like, and is suitable for industrial production.
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Paragraph 0021; 0022; 0023; 0024; 0025
(2018/07/30)
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- Preparation method of diazepam intermediate
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The invention discloses a preparation method of a diazepam intermediate. The method includes the steps of: subjecting an aqueous solution of N-methyl-3-phenyl-5-chloro-2, 1-benzisoxazole methyl quaternary ammonium salt (II) and an aqueous solution of hydrazine hydrate to reduction reaction under the catalysis of a monomethylamine aqueous solution, thus obtaining 2-methylamino-5-chlorobenzophenone(I). Compared with the existing synthetic methods, the method provided by the invention has the advantages of simple synthesis method, high catalytic activity, easy separation and purification of product, high product purity, high yield, low emission of three wastes, small environmental pollution, suitability for industrial production and the like.
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Paragraph 0021; 0022; 0023; 0024; 0025
(2018/07/30)
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- Preparation method of 2-methylamino-5-chlorobenzophenone
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The invention relates to a preparation method of 2-methylamino-5-chlorobenzophenone. The preparation method comprises the following steps: (1) methylation reaction: performing reaction by using 2-amino-5-chlorobenzophenone as a raw material, using sulfuric acid with certain concentration as a solvent and using formaldehyde as a methylation reagent to obtain a methylation reaction solution; (2) neutralization: dropwise adding the methylation reaction solution into a mixed solution of ammonia water with certain concentration and an organic solvent, and performing reflux, cooling and filtration or liquid-separation concentration after dropwise addition is carried out so as to obtain a 2-methylamino-5-chlorobenzophenone crude product; (3) purification: purifying the 2-methylamino-5-chlorobenzophenone crude product through an alcohol solvent to obtain a 2-methylamino-5-chlorobenzophenone refined product. The preparation method disclosed by the invention is simple in process, product post-processing is simple and convenient, and environmental pollution is less; the prepared 2-methylamino-5-chlorobenzophenone product has high quality and is high in stability; therefore, the preparation method is suitable for industrial preparation.
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Paragraph 0020; 0027-0046
(2018/07/30)
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- Transition-Metal-Free Synthesis of Acridones via Base-Mediated Intramolecular Oxidative C?H Amination
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Intramolecular oxidative C?H amination of 2-aminobenzophenones was achieved in the presence of potassium tert-butoxide and dimethyl sulfoxide. A series of functionalized acridones were prepared in moderate to excellent yields in a mild, efficient, and transition-metal-free manner. (Figure presented.).
- Wei, Wen-Tao,Sheng, Jian-Fei,Miao, Hui,Luo, Xiang,Song, Xian-Heng,Yan, Ming,Zou, Yong
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supporting information
p. 2101 - 2106
(2018/06/14)
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- Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow
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Selective N-monomethylation of anilines has been achieved under continuous flow conditions using dimethyl carbonate as a green methylating agent in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process windows available in the continuous flow regime to safely induce monomethylation in superheated solvents at high pressure. We propose selective N-monomethylation is achieved via an in situ protection-deprotection pathway, which is supported by the observed reactivities of several putative reaction intermediates. The robust and scalable method was applicable to a broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized conditions.
- Seo, Hyowon,Bédard, Anne-Catherine,Chen, Willie P.,Hicklin, Robert W.,Alabugin, Alexander,Jamison, Timothy F.
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p. 3124 - 3128
(2017/12/11)
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- Denitrogenative Suzuki and carbonylative Suzuki coupling reactions of benzotriazoles with boronic acids
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Unprecedented palladium-catalyzed denitrogenative Suzuki and carbonylative Suzuki coupling reactions of benzotriazoles with boronic acids have been realized, which afforded structurally diverse ortho-amino-substituted biaryl and biaryl ketone derivatives. The key to this success is due to the development of a rationally designed strategy to achieve the ring opening of benzotriazoles with a synergistic activating-stabilizing effect, which enables the in situ generation of the corresponding ortho-amino-arenediazonium species. The present work opens up a new avenue to utilize benzotriazoles as synthetic equivalents of ortho-amino-arenediazoniums, which otherwise could not be directly accessed by existing synthetic methods.
- Wang, Yuanhao,Wu, Yunfei,Li, Yuanhe,Tang, Yefeng
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p. 3852 - 3857
(2017/07/11)
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- Silica gel-mediated hydroamination/semipinacol rearrangement of 2-alkylaminophenylprop-1-yn-3-ols: Synthesis of 2-oxindoles from alkynes and 1-(2-aminophenyl) ketones
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2-Alkylaminophenylprop-1-yn-3-ols, prepared from the lithium diisopropylamide (LDA)- mediated 1,2-addition of alkynes to 1-(2-aminophenyl) ketones, can be converted to 3,3-disubstituted 2-oxindoles by using silica gel in n-hexane/ ethyl acetate (20:1 v/v) as the reaction medium. The utility of the approach as a potential scale-up strategy for the synthesis of 2-oxindoles was exemplified by the large-scale synthesis of one adduct in excellent yield. The synthetic applicability of this chemistry was also demonstrated by the recycling of the silica gel up to 8 times with no apparent loss of activity being observed for the same example.
- Susanti, Dewi,Ng, Linda Li Ru,Chan, Philip Wai Hong
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supporting information
p. 353 - 358
(2014/05/20)
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- Palladium-catalyzed oxidative C-H bond acylation of N-nitrosoanilines with toluene derivatives: A traceless approach to synthesize N-alkyl-2-aminobenzophenones
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A palladium-catalyzed cascade cross-coupling of N-nitroso-anilines and toluene derivatives for the direct synthesis of N-alkyl-2-aminobenzophenones is described. N-nitroso groups in anilines can act as the traceless directing groups while toluene derivatives can serve as effective acyl precursors under mild reaction conditions.
- Wu, Yinuo,Feng, Ling-Jun,Lu, Xiao,Kwong, Fuk Yee,Luo, Hai-Bin
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supporting information
p. 15352 - 15354
(2015/01/08)
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- Asymmetric synthesis of 1,3-diamines by diastereoselective reduction of enantiopure n-tert-butanesulfinylketimines: unusual directing effects of the ortho-substituent
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(Figure Presented) Chiral, nonracemic 1,3-diamines were prepared in a highly diastereoselective reduction of diaryl N-tert-butanesulfinylketimines. Correlation between facial selectivity of the reduction and E or Z geometry of the starting ketimines suggests involvement of a cyclic transition state for the reduction. The ortho-substituent controls the geometry of N-tert- butanesulfinylketimines in the solid state and provides additional stabilization of the cyclic transition state.
- Martjuga, Marina,Shabashov, Dmitry,Belyakov, Sergey,Liepinsh, Edvards,Suna, Edgars
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supporting information; experimental part
p. 2357 - 2368
(2010/07/02)
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- Bakers' yeast-catalyzed reductive cleavage of 3-aryl-2,1-benzisoxazoles and its quaternary salts: An efficient green synthesis of 2-aminobenzophenones
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3-Aryl-2,1-benzisoxazoles and its salts underwent reductive cleavage of the N-O bond leading to 2-aminobenzophenones with bakers' yeast under non-fermenting conditions in aqueous media. The procedure gives excellent yields of 2-alkylamino- and 2-aminobenzophenones.
- Lekhok, Kushal C.,Prajapati, Dipak,Boruah, Ramesh C.,Mazumder, Sharbani,Borah, Tarun C.
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experimental part
p. 1183 - 1187
(2011/10/01)
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- A novel intramolecular photocyclization of N-(2-bromoalkanoyl) derivatives of 2-acylanilines via 1,8-hydrogen abstraction
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The photochemical reactions of different N-(2-acylphenyl)-2-bromo-2- methylpropanamides have been investigated. Irradiation of the N-unsubstituted anilides 1a-1c gave the corresponding dehydrobromination, cyclization, and bromo-migration products 2, 3, and 4, respectively (Table 1). Irradiation of the N-alkyl anilides 1e-1g afforded the corresponding deacylation and cyclization products 5 and 6, respectively, whereas irradiation of the N-alkyl anilides 1i-1k, carrying 2-benzoyl groups on the aromatic rings, afforded the unexpected tricyclic lactams 7 (besides 2, 5, and 6). The formation of the cyclization products 6 could be rationalized in terms of an electrocyclic ring closure of the 6π-electron-conjugated enamides 2 produced by dehydrobromination of 1, followed by thermal 1,5-acyl migration (Path B in the Scheme). The formation of the bridged lactams 7 probably follows a mechanism involving the 1,7-diradical 8 generated by ζ-H-abstraction (1.8-H transfer) by an excited acyl O-atom (Path A).
- Nishio, Takehiko,Koyama, Hiroyuki,Sasaki, Daigo,Sakamoto, Masami
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p. 996 - 1003
(2007/10/03)
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- Kinetic and mechanistic studies on the hydrolysis and photodegradation of diazepam and alprazolam
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The corresponding o-aminobenzophenones are usually reported as the main degradation products in the hydrolysis of 1,4-benzodiazepinones. Nevertheless, in previous studies of diazepam (DZ) in acidic aqueous medium we isolated and characterized seven unexpected degradation products. Kinetic measurements under several reaction conditions shed some light on the mechanisms of the complex reactions that are taking place, and photochemical studies give hints on the mechanisms of chlorination and annelation processes. Alprazolam (AL) seems to exhibit an unusually high stability against hydrolysis under several conditions; nevertheless, the structure is sensitive to photolytic cleavage. The photodegradation of AL was studied in aqueous and methanolic solutions. Characterization of the isolated products by 1H and 13C NMR and mass spectrometry revealed that electron transfer, oxidation and rearrangement reactions take place. The influence of several variables such as pH, solvent composition and light irradiation were examined and mechanisms for the formation of three photoproducts are proposed. A specific method for the determination of AL in the presence of photoproducts was developed, which allowed kinetic determinations of the photostability of AL. The photosensitivity observed in some patients treated with AL seems to be due to one of the characterized photoproducts. Copyright
- Cabrera, C. Gallardo,Goldberg De Waisbaum,Nudelman, N. Sbarbati
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p. 156 - 161
(2007/10/03)
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- syn/anti Diastereoselectivity in the aldol reaction of aldehydes with the C(3) carbanion of 1,3-dihydro-2H-1,4-benzodiazepin-2-one
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The aldol reaction of the C(3) carbanion of 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (2) with a series of aromatic and aliphatic aldehydes at -78°afforded threo/erythro diastereoisomers 3-16 of 7-chloro-1,3-dihydro-3-(hydroxymethyl)-1-methyl-5-phenyl-2H-1,4- benzodiazepinones, substituted at the C(3) side chain, in a ratio from 55:45 to 94:6 (Scheme 1). Lewis acids exhibited limited effect on the syn/anti diastereoselectivity of this reaction, and kinetic control of the reaction was confirmed. 1H-NMR Data suggested the assignment of the threo relative configuration to the first-eluted diastereoisomers 3, 5 7, and 9 on reversed- phase HPLC, and the erythro configuration to the second-eluted counterparts 4, 6, 8, and 10, respectively. The structures and relative configurations threo and erythro of the diastereoisomers 5 and 6, respectively, were established by single-crystal X-ray analysis, confirming the assignment based on the 1H-NMR data. A tentative mechanistic explanation of the diastereoselectivity invokes the enolate anion of 1,3-dihydro-2H-1,4- benzodiazepin-2-one as the reactive species (Scheme 2). Acid-catalyzed hydrolytic ring opening of 3 afforded threo-β-hydroxy-phenylalanine 17, whereas from 4, the N-(benzyloxy)carbonyl derivative 18 of erythro-β- hydroxy-phenylalanine was obtained (Scheme 3); in both cases, neither elimination of H2O from the C(3)-CHOH moiety nor epimerization at C(3) were observed. This result opens a new pathway to various configurationally uniform α-amino-β-hydroxy carboxylic acids and their congeners of biological importance.
- Markovic, Dean,Hamersak, Zdenko,Visnjevac, Aleksandar,Kojic-Prodic, Biserka,Sunjic, Vitomir
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p. 603 - 615
(2007/10/03)
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- Mechanism of oxidation of diazepam by chloramine-B: A kinetic approach
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The kinetics of the oxidation of diazepam (DZ) by Chloramine-B (CAB) has been studied in aqueous hydrochloric acid medium. The oxidation reaction follows the rate law: -d[CAB]/dt = k[CAB][DZ]0.6[HCl]0.6 The dependence of the reaction rate on temperature is studied and activation parameters for the rate-determining step are evaluated. The dielectric constant of the medium has a small effect on the rate. Ionic strength and the reaction product benzenesulfonamide have no effect on the reaction rate. The solvent isotope effect is studied. A probable mechanism for the observed kinetic data is proposed.
- Nanda,Mayanna,Made Gowda
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p. 605 - 611
(2007/10/03)
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- Kinetic Study of the Reactions of 2-Amino-5-chlorobenzophenone with HCl in MeOH-H2O
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The reaction of 2-amino-5-chlorobenzophenone (1) with 0.5-2 M HCl was studied in 1:1 (v/v) MeOH-H2O at 60 and 80 deg C.Products that were isolated were characterized as 2-(N-methylamino)-5-chlorobenzophenone (2), 2-amino-3,5-dichlorobenzophenone (3), 2-N-methylamino-3,5-dichlorobenzophenone (4), 2-(N,N-dimethylamino)-5-chlorobenzophenone (5), 2,4-dichloro-10-methyl-9,10-acridinone (6) and 2,4-dichloro-9,10-acridinone (7).The rates of reaction of 1 and the rates of formation of 2-5 were measured at several HCl concentrations.The methyl transfers, the chlorination and the cyclization reactions that give rise to 2-7 were unexpected under the present reaction conditions.A set of differential equations was proposed in order to calculate the rate constants for each step of this complex reaction.The proposed reaction scheme also takes into account the reaction 21 and permits the calculation of the rate constants for this reversible reaction.The experimental values of the rate constants for reaction of 1 were compared with those for 2 under the same reaction conditions, in order to evaluate the importance of the methyl group on the methyl transfer reactions; it was found that the methyl group is not required for the unexpected reaction to occur. - Keywords: 2-amino-5-chlorobenzophenone; hydrochloric acid; kinetics
- Nudelman, N. Sbarbati,Waisbaum, R. G. de
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- A convenient method for the production of ortho-amino and N-alkylaminobenzophenones
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ortho-Amino and N-alkylaminobenzophenones 3 have been prepared in good yields by the reductive cleavage of 2,1-benzisoxazole and its salts with Zn-AlCl3*6H2O/THF system.
- Dutta, Dilip Kumar,Konwar, Dilip
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p. 690 - 691
(2007/10/02)
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- Cyclometallated derivatives of palladium(II) with 1,4-benzodiazepin-2-ones. Crystal structure of (L-H)Pd(PPh3)ClCHCl3 (L = Prazepam: 7-chloro-1-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one). Synthesis of isoindolobenzodiazepine derivatives by ...
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The dimeric cyclometallated derivatives of palladium(II) 2, 3 (L = 1, Diazepam: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) and 4 (L = 2, Prazepam: 7-chloro-1-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one) react with triphenylphosphine to give the complexes (L-H)Pd(PPh3)Cl, 5 (L = Diazepam) and 6 (L = Prazepam).The crystal structure of 6 was determined by X-ray crystallography.The palladium atom is in a square planar arrangement.The deprotonated ligand is bound to the metal through the 4-nitrogen and the ortho-carbon atom of the 5-phenyl substituent.The phosphorous and the chlorine atoms are trans to the nitrogen and the carbon atoms, respectively: Pd-N = 2.085(2), Pd-P = 2.263(1), Pd-Cl = 2.377(1), Pd-C = 2.009(3) Angstroem.The reaction of the dimeric derivatives 2 with carbon monoxide was investigated.Under mild conditions (1 atm of CO, room temperature) the unstable (L-H)Pd(CO)Cl derivatives, 7 (L = Diazepam) and 8 (L = Prazepam) are formed, but at high pressure and temperature (60-100 atm of CO, 45-50 deg C), extrusion of palladium occurs and tetracyclic derivatives having an isoindolo ring condensed on the 1,4-benzodiazepin-2-one system, 9-12, are obtained.
- Cinellu, Maria Agostina,Gladiali, Serafino,Minghetti, Giovanni,Stoccoro, Sergio,Demartin, Francesco
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p. 371 - 384
(2007/10/02)
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- Micellar Catalysis of Organic Reactions. 18. Basic Hydrolysis of Diazepam and Some N-Alkyl Derivatives of Nitrazepam
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Kinetic and mechanistic studies of the basic hydrolysis of several benzodiazepinone drugs have been carried out in the presence of micelles of cetyltrimethylammonium bromide (CTAB) and in aqueous solution.For diazepam, a change of mechanism from initial azomethine hydrolysis in water to initial amide hydrolysis in the presence of micelles of CTAB is indicated.For nimetazepam and N-benzylnitrazepam, initial amide hydrolysis was observed both in the presence of CTAB and in water.For the latter compounds, strong catalysis (50-100) of amide hydrolysis (phase 1) by micelles of CTAB was observed, while azomethine hydrolysis (phase 2) was only very weakly catalyzed (3-4-fold).For diazepam, the catalysis was smaller (9-18-fold), but this was accompanied by a mechanistic change so that here the actual catalysis of amide hydrolysis is masked.
- Broxton, Trevor J.,Wright, Sallyanne
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p. 2965 - 2969
(2007/10/02)
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- A Convenient Preparation of Alkylaminobenzophenones from 2,1-Benzisoxazolium Salts and Iodotrimethylsilane
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2-Alkylaminobenzophenones (2) have been prepared in good yields from 2,1-benzisoxazolium salts (1) and iodotrimethylsilane.
- Konwar, D.,Boruah, R. C.,Sandhu, J. S.
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p. 975 - 976
(2007/10/02)
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- Screening, detection and biotransformation of lormetazepam, a new hypnotic agent from the 1,4-benzodiazepine series
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The paper describes a screening procedure for 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-2,3-dihydro-1H-1,4-benzodiaze pin-2-one (lormetazepam, Noctamid) and other important analytical data (TLC, GLC, UV-, IR- and mass spectra) of this new benzodiazepine derivative. Screening results after a single p.o. dose of 1 mg lormetazepam (Noctamid-1) are also reported.
- Schutz,Fitz
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p. 177 - 183
(2007/10/02)
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- N-Substituted (Sarcosylamino)benzophenones. Their Synthesis and Conversion into Heterocycles
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A synthetic study of N-substituted (sarcosylamino)benzophenones 2 is described.The target molecules 2 were found to be reactive under neutral conditions, affording intramolecularly cyclized products.Compounds 6a and 13a were converted into pyrazinoquinazoline 9a and pyrazinoquinoline 18a, respectively.The new heterocycles were characterized, and possible mechanisms are proposed for their formation.
- Hirai, Kentaro,Ishiba, Teruyuki,Sugimoto, Hirohiko,Fujishita, Toshio
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p. 4489 - 4493
(2007/10/02)
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- New Synthesis of Diazepam
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An efficient preparation of 7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione from 5-chloro-N-methylisatoic anhydride and glycine has been devised, and from it, by the action of phenylmagnesium chloride on its N-acetyl-derivative followed by treatment with hydroxylamine and cleavage of the resulting desacetyl oxime with sodium bisulfite, diazepam has been synthesized.The overall yield is about 50percent from 5-chloroisatoic anhydride.
- Gates, Marshall
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p. 1675 - 1681
(2007/10/02)
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