Synthesis of 2-methylcarbamazepine,a new internal standard for chromatographic assays of carbamazepine (tegretol®)

The synthesis of 2-methyl-5H-dibenz[b,f]azepine-5-carboxamide (2-methylcarbamazepine, 2-MCBZ, 8), a promising internal standard for chromatographic assays of the antiepileptic agent carbamazepine (CBZ, 1), is described. N-(p-Tolyl)anthranilic acid (2) was utilized as a starting material for the synthesis of a key compound, 2,9-dimethylacridine (4), which was converted in two steps to 2-methyl-9-hydroxymethylacridan (6). The acridan 6, in the presence of poly-phosphoric acid, was ring-expanded to form 2-methyl-5H-dibenz[b,f]azepine (7), this latter compound being converted by conventional reactions to its 5-carbamyl derivative, 2-MCBZ (8).     

微波固相法合成钠快离子导体Na5YSi4O12

应用微波方法合固相反应难于制备的Ｎａ５ＹＳｉ４Ｏ１２纯相，讨论了微波合成条件对产物的影响，与溶胶－凝胶法相比，微波法反应速率快，选择性强，合成的样品具有特异的聚集态，缺陷和微结构，从而导致离子导电活化能下降。     

Determination of carbamazepine by chemiluminescence detection using chemically prepared tris(2,2'-bipyridine)ruthenium(III) as oxidant.

A new chemiluminescence method for the determination of carbamazepine (CBZ) has been developed. The method is based on the chemiluminescence produced in the reaction of tris(2,2'-bipyridine)ruthenium(III) and CBZ in an acidic medium. The chemiluminescence intensity was enhanced by organic solvents in the reaction system. Under the optimum experimental conditions, the calibration curve was linear over the range 4.0 x 10(-3)-8.6 x 10(-7) mol/L for CBZ. The detection limit (S/N = 3) was 2.5 x 10(-7) mol/L and the relative standard deviation of six replicate measurements was 2.6% for 4.0 x 10(-4) mol/L of CBZ. The possible reaction mechanism were also discussed. The chemiluminescence method was successfully applied to assay the CBZ contents in pharmaceutical tablets.     

Simultaneous separation and determination (in serum) of phenytoin and carbamazepine and their deuterated analogues by high-performance liquid chromatography--ultraviolet detection for tracer studies

The use of stable isotope-labeled tracer compounds is the safest and most effective method to perform many steady state pharmacokinetic and drug interaction studies. We describe a method by which the heavily deuterated 2H10 analogues of carbamazepine (2H10 CBZ) and phenytoin (2H10 PHT) can be chromatographically separated by high-performance liquid chromatography from unlabeled CBZ and PHT. All compounds are quantitated against an internal standard (IS) (10,11-dihydrocarbamazepine) and measured using conventional UV detection rather than mass spectrometry. Baseline resolution of extracted serum containing 2H10 CBZ, CBZ, 2H10 PHT, PHT and IS is achieved on a heated (55 degrees C) 25 cm x 4.6 mm BioAnalytical Systems Phase II 5 microns ODS column with an isocratic mobile phase consisting of water-acetonitrile-tetrahydrofuran (80:16:4, v/v/v) at 1.2 ml/min. Eluting compounds were monitored at a UV wavelength of 214 nm. Calculated resolution of 2H10 CBZ from CBZ and of 2H10 PHT from PHT were 1.3. Serum standard curves were linear (R greater than or equal to 0.999) over a range of 0.5-14 micrograms/ml for 2H10 CBZ, 0.5-20 micrograms/ml for CBZ, 0.5-20 micrograms/ml for 2H10 PHT, and 0.5-30 micrograms/ml for PHT. Within-day percent relative standard deviations (precision) were less than 6% in all cases.     

EDTA冠醚衍生物——Ⅷ.两个长桥链双冠醚的合成

前文报道的由EDTA桥联的水溶性双冠醚,虽然对碱土金属离子的配位有其特点,但可能是由于桥键不够长和二个刚性苯环的存在,桥键上两个羧甲基不但不起配位协同作用,反而阻碍了两个冠醚环的靠近,从而未显示出预期的高络合特性。为此,我们按下式合成了两个更长桥键的双冠醚1和2:     

Synthesis of N‐Benzylated Anilines from the Reaction of Anilines and Benzyl Chloroformate

Abstract

Reactions of benzyl chloroformate with a series of substituted anilines produced N‐carbobenzyloxy “CBZ” products along with the unexpected N‐benzylated “Bn” compounds. Reaction of aniline, 1a, gave the CBZ, or 2a, and Bn, or 3a, products in 29% and 14% yield, respectively. For 2‐nitro‐, 2‐bromo‐, and 2‐bromo‐5‐nitroanilines, the N‐benzylated compounds were produced exclusively. However, 2‐methoxy‐, 4‐bromo, 4‐iodo, and 4‐ethylanilines gave mainly CBZ products. Other compounds reported in this study gave mixtures of the two products. For 4‐chloro‐3‐nitroaniline, in addition to the Bn and CBZ products (53% and 14% yield, respectively), a N,N‐dibenzylated product was isolated in 27% yield. Collectively, the results indicated that electron‐withdrawing groups, particularly at the ortho position, directed the formation of Bn compounds, whilst electron‐donating groups, especially at the ortho and para positions, favored the synthesis of CBZ products.     

A New and Concise Synthesis of 3-Hydroxybenzo[c]phenanthrene and 12-Hydroxybenzo[g]chrysene, Useful Intermediates for the Synthesis of Fjord-Region Diol Epoxides of Benzo[c]phenanthrene and Benzo[g]chrysene

A new strategy which involves a palladium-catalyzed cross-coupling reaction has been developed for the rapid synthesis of 3-hydroxybenzo[c]phenanthrene (5) and 12-hydroxybenzo[g]chrysene (6). These phenolic compounds are the key intermediates for the synthesis of highly carcinogenic fjord-region diol epoxide metabolites 3 and 4 of benzo[c]phenanthrene (1) and benzo[g]chrysene (2). The cross-coupling reaction of 2-bromo-5-methoxybenzaldehyde (9) with naphthalene-1-boronic acid (7) and phenanthrene-9-boronic acid (8) produced 2-(1-naphthyl)-5-methoxybenzaldehyde (10) and 2-(9-phenanthryl)-5-methoxybenzaldehyde (11), respectively, in quantitative yields. After reaction of these aldehydes with trimethylsulfonium iodide under phase-transfer conditions or with the Wittig reagent obtained from (methoxymethyl)triphenylphosphonium bromide and phenyllithium to generate an oxiranyl or methoxyethene side chain, the acid-catalyzed cyclization with methanesulfonic acid (or boron trifluoride) produced 3-methoxybenzo[c]phenanthrene (16) and 12-methoxybenzo[g]chrysene (17) in 61-64% yields. Finally, demethylation of these methoxy derivatives 16 and 17 with boron tribromide resulted in the formation of the hydroxy analogues 5 and 6, respectively. The availability of this short and high-yielding regiospecific method for the synthesis of phenols 5 and 6 should allow the preparative-scale synthesis of the fjord-region diol epoxides 3 and 4. These diol epoxides are required as starting compounds for the synthesis of site-specifically modified oligonucleotides which are critically needed to elucidate the mechanism of carcinogenesis at the molecular level.     

Second-order advantage with excitation–emission photoinduced fluorimetry for the determination of the antiepileptic carbamazepine in environmental waters

A photochemically induced fluorescence system combined with second-order chemometric analysis for the determination of the anticonvulsant carbamazepine (CBZ) is presented. CBZ is a widely used drug for the treatment of epilepsy and is included in the group of emerging contaminant present in the aquatic environment. CBZ is not fluorescent in solution but can be converted into a fluorescent compound through a photochemical reaction in a strong acid medium. The determination is carried out by measuring excitation–emission photoinduced fluorescence matrices of the products formed upon ultraviolet light irradiation in a laboratory-constructed reactor constituted by two simple 4 W germicidal tubes. Working conditions related to both the reaction medium and the photoreactor geometry are optimized by an experimental design. The developed approach enabled the determination of CBZ at trace levels without the necessity of applying separation steps, and in the presence of uncalibrated interferences which also display photoinduced fluorescence and may be potentially present in the investigated samples. Different second-order algorithms were tested and successful resolution was achieved using multivariate curve resolution-alternating least-squares (MCR-ALS). The study is employed for the discussion of the scopes and yields of each of the applied second-order chemometric tools. The quality of the proposed method is probed through the determination of the studied emerging pollutant in both environmental and drinking water samples. After a pre-concentration step on a C18 membrane using 50.0 mL of real water samples, a prediction relative error of 2% and limits of detection and quantification of 0.2 and 0.6 ng mL⁻¹ were respectively obtained.     

Asymmetric synthesis of 2-amino-3-hydroxynorbornene-2-carboxylic acid derivatives

The enantioselective synthesis of 2-amino-3-hydroxynorbornene-2-carboxylic acid derivatives (5) was studied using the Diels-Alder reaction between cyclopentadiene and different dienophiles, i.e., alkyl 5-oxo-2-phenyloxazol-4-methylenecarbonates (1) or 2-benzoylamino-3-alkoxycarbonyloxy-acrylates (12), operating with different Lewis acids and both with thermal and with ultrasound conditions. The enantioselective synthesis of the exo/endo compounds 5c,d and 5'c,d was achieved starting from the chiral menthyl acrylates 12b,c using Mg(ClO(4))(2) as the catalyst and ultrasound. The cycloadducts were obtained in very good yield, in mild conditions, in short time, and in good diastereomeric excess (exo, 80%; endo, 87%). Finally, the use of alkylidene-oxazolones or acrylates and EtAlCl(2) or Mg(ClO(4))(2) as the catalyst allowed control of the cycloaddition reaction in favor of the exo or endo products.     

Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides

A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.     

Total synthesis of (+/-)-2-isocyanoallopupukeanane

2-Isocyanoallopupukeanane (4) has been obtained in racemic form from methyl 2-exo-methylbicyclo[2.2.1]hept-5-ene-2-endo-carboxylate via dibromocarbene addition, S(N)2' displacement, chain extension, and elaboration of the unsaturated ketone 12c which underwent an intramolecular hetero-Diels-Alder reaction to afford 13 containing all the skeletal carbon atoms. The dihydropyran unit was cleaved by ozonolysis to give the tricarbocyclic intermediate which required seven more steps to complete the synthesis.     

4′-{2-[5-(4-羧基苯基)呋喃基]}-2,2′:6′,2″-三联吡啶的合成——推荐一个大学有机化学实验

介绍一个面向大学高年级本科生的综合性有机化学实验——4′-{2-[5-(4-羧基苯基)呋喃基]}-2,2′:6′,2″-三联吡啶的合成与结构表征。以糠醛、对氨基苯甲酸为原料经低温条件下的偶联反应制备5-(4-羧基苯基)呋喃-2-甲醛,并以其和2-乙酰基吡啶为原料,在碱性条件下以氨水为氮源合成目标产物。通过熔点测定、红外光谱和核磁共振氢谱对其结构进行表征。该实验合成路线成熟,包括芳环偶联、α,β-不饱和酮的合成、Michael加成等内容,能达到多方面对学生进行锻炼之目的,是一个值得推荐的有机化学实验。     

Ring closure reaction of 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride. Synthesis of pyrimido[5,4-c] [1,5]benzoxazepin-5(11H)ones

Syntheses of 11-acety1-2-phenylpyrimido[5,4-c][1,5]benzoxazepin-5(11H)one ( 16a ) and analogs ( 16b,c, 22 ) were described. The reaction of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 7 ) with 2-aminophenol afforded 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester ( 8a ). The latter was also prepared by catalytic reduction of 4-(2-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 9 ), which was obtained from 7 and 2-nitrophenol. Involvement of 4-(2-aminophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 12a ) in this reduction as an intermediate was demonstrated by an independent synthesis of 12a and its subsequent rearrangement to 8a. Hydrolysis of 8a or 12a gave 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid ( 15a ). Reaction of 15a with acetic anhydride afforded 16a , the first member of a novel ring system, the pyrimido[5,4- c ][1,5]-benzoxazepin. Additional examples ( 16b,c ) were prepared similarly. The corresponding 11-ethyl derivative ( 22 ) was prepared in similar fashion, starting with 7 and 2-ethylaminophenol. A possible reaction mechanism for the formation of 16a-c from 15a-c and acetic anhydride was discussed.     

A formal total synthesis of roseophilin: cyclopentannelation approach to the macrocyclic core

[formula: see text] The formal total synthesis of the macrocyclic core of roseophilin 4 has been accomplished in 12 steps from 5-hexenal 8. The cyclopentannelation reaction was used to form the aliphatic five-membered ring of 3. Diene 2 was assembled by means of a Stetter reaction. Ring-closing metathesis of 2, reduction, and Knorr reaction of the 1,4-diketone 5 gave the ketopyrrole 3.     

New cocrystals of heterocyclic drugs: structural,antileishmanial, larvicidal and urease inhibition studies

Many heterocycles have been developed as drugs due to their capacity to interact productively with biological systems. The present study aimed to synthesize cocrystals of the heterocyclic antitubercular agent pyrazinamide ( PYZ , 1 , BCS III) and the commercially available anticonvulsant drug carbamazepine ( CBZ , 2 , BCS class II) to study the effect of cocrystallization on the stability and biological activities of these drugs. Two new cocrystals, namely, pyrazinamide–homophthalic acid (1/1) ( PYZ:HMA , 3 ) and carbamazepine–5-chlorosalicylic acid (1/1) ( CBZ:5-SA , 4 ), were synthesized. The single-crystal X-ray diffraction-based structure of carbamazepine–trans-cinnamic acid (1/1) ( CBZ:TCA , 5 ) was also studied for the first time, along with the known cocrystal carbamazepine–nicotinamide (1/1) ( CBZ:NA , 6 ). From a combination drug perspective, these are interesting pharmaceutical cocrystals to overcome the known side effects of PYZ ( 1 ) therapy, and the poor biopharmaceutical properties of CBZ ( 2 ). The purity and homogeneity of all the synthesized cocrystals were confirmed by single-crystal X-ray diffraction, powder X-ray diffraction and FT–IR analysis, followed by thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed intermolecular interactions and the role of hydrogen bonding towards crystal stability were evaluated quantitatively via Hirshfeld surface analysis. The solubility of CBZ at pH 6.8 and 7.4 in 0.1 N HCl and H₂O were compared with the values of cocrystal CBZ:5-SA ( 4 ). The solubility of CBZ:5-SA was found to be significantly improved at pH 6.8 and 7.4 in H₂O. All the synthesized cocrystals 3 – 6 exhibited a potent urease inhibition (IC₅₀ values range from 17.32 ± 0.89 to 12.3 ± 0.8 µM), several times more potent than standard acetohydroxamic acid (IC₅₀ = 20.34 ± 0.43 µM). PYZ:HMA ( 3 ) also exhibited potent larvicidal activity against Aedes aegypti. Among the synthesized cocrystals, PYZ:HMA ( 3 ) and CBZ:TCA ( 5 ) were found to possess antileishmanial activity against the miltefosine-induced resistant strain of Leishmania major, with IC₅₀ values of 111.98 ± 0.99 and 111.90 ± 1.44 µM, respectively, in comparison with miltefosine (IC₅₀ = 169.55 ± 0.20 µM).     

Total synthesis of rutamycin B and oligomycin C

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.     

Synthesis of Phenylalanine Analogs

A straightforward synthesis of phenylalanine analogs is described. Cerium ammonium nitrate (CAN) mediated addition of azide to cinnamic ester, followed by reaction with sodium acetate afforded the α‐azidocinnamate in moderate yield. Hydrogenation of α‐azidocinnamate, followed by BOC, CBZ or Fmoc protection gave phenylalanine analogs. A new approach for synthesizing racemic p‐boronophenylalanine analog was also explored.     

An efficient synthesis of cholanic acids from 20-ketopregnanes

An efficient synthesis of 3β-hydroxy-5-cholanic acid (8) and 3β-hydroxy-Δ⁵-cholanic acid (16) was carried out starting from 5-dihydropregnenolene (1) and pregnenolone (9). The monoacetates (3 and 11), prepared by Grignard reaction of 1 and 9 with 3,3-ethylenedioxypropylmagnesium bromide followed by acetylation, were dehydrated selectively to give the Δ²⁰⁽²²⁾-compounds (4 and 12) which on hydrogenation followed by acid treatment and Jones oxidation yielded 8 and 16, respectively.     

Construction of an enantiomerically pure 6-substituted 3,5-syn-dihydroxyhexanoic acid system by an enantioselective deprotonation strategy: formal synthesis of an antiobesity agent, (-)-tetrahydrolipstatin

Preparation of 6-substituted 4-hydroxytetrahydro-2H-pyran-2-one (12), a key intermediate for the synthesis of (-)-tetrahydrolipstatin, was achieved in an optically pure form by employing an enantioselective deprotonation reaction of the prochiral bicyclic derivative (5) as a key step.