Catalytic hydrogenation on Raney nickel of estra-1,3,5(10),8,14-pentaenes with sterically accessible double bonds

The catalytic hydrogenation of estra-1,3,5(10),8,14-pentaenes with sterically accessible double bonds in the presence of Raney nickel in 2-propanol at elevated pressure and at heating to 110–120°C resulted in prevailing formation of estrogens 8α-analogs alongside a considerable quantity of estra-5,7,9-trienes. Although the hydrogenation at 45–60°C provided a higher yield of estrogens 8α-analogs, the synthesis of steroids of this group gave better results at hydrogenation in a high purity benzene.     

Syntheses of derivatives of oestrane and 19-norsteroids from 6-methoxytetralone and 6-hydroxytetralone

The corresponding derivatives of Δ^{1,3,5(10),9,(11)}-8,14-seco- -homo-oestratetraen-3-ol-14,17a-dione(VII, VIII, IX) have been obtained by the condensation of 3-methoxy-, 3-hydroxy-, and 3-tetrahydropyranyloxy-1-vinyltetralols (IV, V, VI) with methyldihydroresorcinol. The diketones VIII and IX cyclize to form Δ^{1,3,5(10),8,14}- -homo-oestrapentaen-3-ol-17a-one (XIII), and the diketone (VII) may be converted, according to conditions, into 3-methoxy-Δ^{1,3,5(10),8,14}- -homo-oestrapentaen-17a-one (X), 3-methoxy-Δ_{1,3,5(10),9,(11)}- -homo-oestratetraen-14-ol-17a-one (XIV), and -homoequilenin (XI). Hydrogenation of the ketones X and XIII leads to the dihydroketones XV and XVI with a trans junction of the C and D rings. Reduction or hydrogen of XV gives the methyl ethers of -homo-oestrone and 8-iso- -homo-oestrone XIX and XVII which have been converted into the methyl ethers of (±)-oestrone and 8-iso-oestrone (XX and XXI). 19-Nor- -homotestosterone (XXV) and its methyl and ethyl analogues, which possess anabolic activity, have been obtained by a series of reactions from the ketones X and XV.     

Totally synthetic steroid heterocycles. Part 7.. A facile approach to 16-oxa-D-homoestrogens

In search of biologically active modified steroids, novel 16-oxa-D-homoestrone and -D-homoestradiol 3-methyl ethers were synthesized from 16-oxa-3-methoxy- D -homoestra-1,3,5(10),8,14-pentaen-17a-one. The straightforward synthesis involved stereoselective two-step reduction of the 8,14-diene system. The B/C stereoisomers were also derived from the estrapentaene. The stereostructures of these heterocyclic estrogens were determined on the basis of their spectral data.     

Preparation of derivatives of DL-estrone and of 19-norsteroids from 3-methoxy-Δ1,3,5,(10),9(11)-8,14-secoestratetraen-14,17-dione

Summary Starting from S-methoxy-^{1,3,5(10),8,14}-estrapentaen-17-one (II) and its ethylene ketal (III), a combination of hydrogenation, reduction by Birch's and Johnson's methods, and other reactions has given the methyl ethers of DL-estrone and DL-estradiol (I) and (XV), and also DL-19-nortestosterone (XVI), ^4,8-19-norandrostadienedione (VIII) and other steroids.     

Synthesis of 6-oxaestra-1,3,5(10),8,14-pentaenes

The Wendler version of the Torgov-Ananchenko scheme of total steroid synthesis was shown to be applicable to the preparation of 6-oxaestra-1,3,5(10),8,14-pentaenes. Conditions for cyclodehydration of secosteroids thus obtained were found, which ensured isolation of the target compounds in a high yield without using chromatographic purification methods.     

New analogs of D-homoequilenine with substituents in the D ring

Stereoselectivity of reaction with Raney nickel of D-homoestra-1,3,5(10),8,14-pentaenes containing one or two methyl groups in position 16 was investigated. The reaction direction is governed by the orientation of the substituent at C^17a. The signals in the ¹H and ¹³C NMR spectra of four synthesized compounds were completely assigned. Criteria for evaluation of the character of rings junction in analogs of D-homoequilenine were suggested. 16,16-Dimethyl-3-methoxy-D-homo-13α-estra-1,3,5(10),6,8-pentaen-17a-one was subjected to X-ray diffraction analysis.     

Cyclization of 3-methoxy-8, 14-seco-D-homoestra-1, 3, 5(10), 9(11)-tetraene-14, 17a-dione into D-homoestrone derivatives

Conclusions In the cyclization of 3-methoxy-8, 14-seco-D-homoestra-1,3,5,(10),9(11)-tetraene-14, 17a-dione (I) the stereoisomeric 14-hydroxy-3-methoxy-D-homoestra-1,3,5(10),9(11)-tetraen-17a-ones (III) and (IV) are formed at first, and after dehydration and isomerization these are converted into 3-methoxy-D-homoestra-1,3,5(10),8,14-pentaen-17a-one (II). The ketol (IV) is much more readily dehydrated than the ketol (III) and is probably themain intermediate product in the cyclization of the diketone (I).Translated from Izvestiya Akadeemii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1413–1416, August, 1965 Original article submitted June 24, 1963     

The total synthesis and anti-fertility activity of 6-silasteroids

4,4-Dimethyl-6-methoxy-4-sila-1-tetralone (2) was prepared by a modified literature procedure and converted to 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8,14-pentaen-17β-yl acetate (5c). Catalytic hydrogenation of 5c gave 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8-tetraen-17β-yl acetate (6b), and its 14-iso- and Δ^{1,3,5(10),8(14)} isomers, the proportions varying with the catalyst and solvent. Reduction of 6b with lithium-liquid ammonia, and O-demethylation, gave 6,6-dimethyl-6-silaestradiol (8b). Reduction of the 3-methyl ether of 8b with lithium-liquid ammonia-t-butanol and hydrolysis afforded 3-keto-6,6-dimethyl-6-silaestr-1(10)-en-17β-ol (15), which was catalytically reduced to its 1,10α-dihydro derivative 17. The 5,6 SiC bond of 8b, 15 and their derivatives was cleaved by boron tribromide, aq. ethanolic hydrogen fluoride, and other reagents, providing a series of 5,6-seco-6,6-dimethyl-6-silasteroids. X-ray crystallographic analysis of 17 and the 17α-ethynyl derivative of 15 confirmed the stereochemical assignments. None of the compounds which were subjected to uterotropic, anti-uterotropic, or post-coital assays, showed significant activity. A partially completed synthesis of 6-silaestradiol (21a) is described.     

Ionic Hydrogenation of 8-Aza-16-thiagona-1,3,5(10),13-tetraene-12,17-diones. Synthesis and Properties of 8-Aza-16-thiagona-1,3,5(10),13-tetraen-17-ones

Ionic hydrogenation of 8-aza-16-thiagona-1,3,5(10),13-tetraene-12,17-diones has been carried out by regioselective reduction of the carbonyl part of the aminovinylketothiolactone group to give 8-aza-16-thiagona-1,3,5(10),13-tetraen-17-ones.     

14-methyl steroids. Part 3. Synthesis of (±)-14α-methyl-9β-estradiol and related 14α-methyl-19-norsteroids

Catalytic hydrogenation of a totally synthetic mixture of (±)-3-methoxy-14-methyl-14α-estra-1,3,5( 10), 9(11)-tetraen-17-one(1) and the corresponding 1,3,5(10),8-tetraen-17-one (2) gives a mixture of 14α-methyl-8β,9β-, -8α,9α-, and -8β,9α-estrones, which is converted into the 17β-hydroxy-mixtures. t-Butylation gives a separable mixture of the three isomers, of which (±)-17β-t-butoxy-3 methoxy-14-methyl-9β,14α-estra-1,3,5(10)-triene(6) is the major component. The corresponding 14α-methylestradiols are prepared. A practical synthesis of (±)-14-methyl-14α-estra-1,3,5(10), 6,8-pentaene-3,17β-diol(25) is described, and it is shown that DDQ dehydrogenation of 1,3,5(10),9(11)-tetraenes in this series leads exclusively to the corresponding 1,3,5(10),6,8,11-hexaenes, whereas that of 1,3,5(10),8-tetraenes gives only 1,3,5(10),6,8-pentaenes.     

The synthesis of some D-homosteroids

Summary Starting from 3-methoxy-^{1,3,5(11),8,14}-D-homoestrapentaen-17a-one (IV), a four-stage synthesis has yielded (±)-19-nor-D-homotestosterone (IX) and its esters, which possess anabofic activity.     

Synthesis and molecular structure study of 3-methoxy-7α-methyl-6-oxa-9β,14β-estra-1,3,5(10)-trien-17-one in solution

It was established by NMR spectroscopy that the catalytic hydrogenation of 3-methoxy-7α-methyl-6-oxa-14β-estra-1,3,5(10),8-tetraen-17-one leads to the formation of 3-methoxy-7α-methyl-6-oxa-9β,14β-estra-1,3,5(10)-trien-17-one, the structure of which was investigated in solution. The corresponding analog with a free hydroxyl group at the position 3 possesses an antiradical activity at the absence of uterotropic effect.     

The composition of transformation products of 2,4,6-trinitrobenzoic acid in the aqueous-phase hydrogenation over Pd/C catalysts

Due to a detailed analysis of NMR spectra of the reaction solutions with different composition obtained by the aqueous-phase catalytic (Pd/C) hydrogenation of 2,4,6-trinitrobenzoic acid, the intermediate compounds were identified and a more substantiated mechanism was proposed for the formation of the main reaction products—1,3,5-triaminobenzene and cyclohexane-1,3,5-trione trioxime. The condensation of the 1,3,5-triaminobenzene molecules produced by a complete hydrogenation of 2,4,6-trinitrobenzoic acid was shown to result in the formation of a paramagnetic heterocyclic compound.     

An unusual reduction route of 2,4,6-trinitrobenzoic acid under conditions of aqueous-phase hydrogenation over Pd/Sibunit catalyst

For the first time it was established that the catalytic hydrogenation of 2,4,6-trinitrobenzoic acid to 1,3,5-triaminobenzene can proceed via the formation of aromatic hydroxyamines and cyclohexane-1,3,5-trione trioxime. As a result of aqueous-phase hydrogenation of sodium salt of 2,4,6-trinitrobenzoic acid in the presence of 5%Pd/Sibunit catalyst at a temperature of 323 K and pressure of 0.5 MPa, a trioxime in high yield (about 70 %) was obtained. Due to high selectivity to cyclohexane-1,3,5-trione trioxime the catalytic hydrogenation of sodium salt of 2,4,6-trinitrobenzoic acid can be considered as a new method for its synthesis.     

Total synthesis of the 6-silasteroid ring system

The total synthesis of the first¹ silasteroid ring system is described. A bidirectional construction was employed, starting from precursors of rings A and D. Metal-organic substitutions on dimethyldichlorosilane gave the allyl-m-methoxyphenyl derivative 2, as elements of rings AB. Hydroboration-oxidations led to the arylsilylpropionic acid 5. Activation and cyclization gave the key intermediate, 4,4 - dimethyl - 4 - sila - 6 - methoxy - 1 - tetralone, 7. Attachment of ring D and closure of ring C followed the Torgov-Smith outline, but required important differences in implementation, to give D,L-6, 6 - dimethyl - 6 - sila - 3 - methoxy - estra - 1,3,5(10),8,14 - pentaene - 17 - one, 11. Extensive physical data are presented.     

Synthesis of 4-amino-6-chloro-1,3,5-triazin-2(1H)-ones

Conditions for selective substitution for one chlorine atom in 2-(R,R??-amino)-4,6-dichloro-1,3,5-triazines with a hydroxide ion were elaborated. Spectral and calculation methods showed that the products formed are in the lactam form, i.e., have the structure of 4-chloro-6-(R,R??-amino)-1,3,5-triazin-2(1H)-ones.     

Heat capacities and thermodynamic properties of M(HBTC)(4,4′-bipy)·3DMF (M?=?Ni and Co)

Two metal?Corganic frameworks (MOFs) of M(HBTC)(4,4??-bipy)·3DMF [M?=?Ni (for 1) and Co (for 2); H₃BTC?=?1,3,5-benzenetricarboxylic acid (1,3,5-BTC); 4,4??-bipy?=?4,4??-bipyridine; DMF?=?N,N??-dimethylformamide] were synthesized by a one-pot solution reaction and a solvothermal method, respectively, and characterized by powder X-ray diffraction and FT-IR spectra. The low-temperature molar heat capacities of M(HBTC)(4,4??-bipy)·3DMF were measured by temperature-modulated differential scanning calorimetry (TMDSC) for the first time. The thermodynamic parameters such as entropy and enthalpy relative to reference temperature 298.15?K were derived based on the above molar heat capacity data. Moreover, the thermal stability and the decomposition mechanism of M(HBTC)(4,4??-bipy)·3DMF were investigated by thermogravimetry analysis (TGA). The experimental results through TGA measurement demonstrate that both of the two compounds have a three-stage mass loss in air flow.     

Development of an efficient method for preparation of 1,3,5-trihydroxyisocyanuric acid (THICA) and its use as aerobic oxidation catalyst

1,3,5-Trihydroxyisocyanuric acid (THICA), which serves as an efficient radical-producing catalyst from hydrocarbons, was successfully prepared by two methods. The reaction of O-benzylhydroxyamine with phenyl chloroformate gave formbenzyloxycarbamic acid phenyl ester of which subsequent treatment with dimethylaminopyridine (DMAP) produced 1,3,5-tribenzyloxyisocyanurate leading to THICA by hydrogenation with H₂ on Pd/C. The other method involved the direct synthesis of 1,3,5-tribenzyloxyisocyanurate from O-benzylhydroxyamine and diphenyl carbonate. The aerobic oxidation of p-methylanisole catalyzed using THICA as a key catalyst afforded p-anisic acid in almost quantitative yield (>99%).     

2,4,6-三对氨基苯氧基-1,3,5-均三嗪的合成

以三聚氯氰和对硝基苯酚为原料,经取代、还原合成了2,4,6-三对氨基苯氧基-1,3,5-均三嗪。对Pd/C水合肼、SnCl2·2H2O-HCl及Pd/C催化加氢三种不同还原体系进行比较。采用1H-NMR、FT-IR和元素分析方法对产物进行结构表征。     

Rapid and Simultaneous Determination of Efavirenz, 8-Hydroxyefavirenz, and 8,14-Dihydroxyefavirenz Using LC�CMS�CMS in Human Plasma and Application to Pharmacokinetics in Healthy Volunteers

We developed a rapid and sensitive method for determining efavirenz, 8-hydroxyefavirenz, and 8,14-dihydroxyefavirenz in human plasma simultaneously using liquid chromatography?Ctandem mass spectrometry (LC?CMS?CMS). Three compounds and ritonavir, an internal standard, were extracted from plasma using ethyl acetate in the presence of 0.1 M sodium carbonate after incubation of ??-glucuronidase (500 U). After drying the organic layer, the residue was reconstituted in mobile phase (acetonitrile:20 mM ammonium acetate, 90:10, v/v) and injected onto a reversed-phase C₁₈ column. The isocratic mobile phase was eluted at 0.2 mL min^?1. The ion transitions monitored in multiple reaction-monitoring mode were m/z 314 ?? 244, 330 ?? 258, 346 ?? 262, and 721 ?? 296 for efavirenz, 8-hydroxyefavirenz, 8,14-dihydroxyefavirenz, and ritonavir, respectively. The retention time is 1.93, 1.70, 1.52, and 1.82 min for efavirenz, 8-hydroxyefavirenz, 8,14-dihydroxyefavirenz, and ritonavir, respectively. The coefficients of variation of the assay precision were less than 10.7%, and the accuracy was 90?C111%. The lower limits of quantification (LLOQ) were 5 ng mL^?1 for efavirenz and 8-hydroxyefavirenz. This method was used to measure the plasma concentrations of efavirenz and its metabolites from healthy volunteers after a single 600 mg oral dose of efavirenz. This analytical method is a very rapid, sensitive, and accurate to determine the pharmacokinetic profiles of efavirenz including its metabolites.