Exemestane: Synthesis, Chemical Analysis, Reactions

Das Enzym Aromatase katalysiert die Umwandlung der Androgene Testosteron und Androst-4-en-3,17-dion in die Estrogene Estradiol und Estron. Exemestan (6-Methylen-androsta-1,4-dien-3,17-dion) (9) ähnelt strukturell dem natürlichen Substrat Androst-4-en-3,17-dion, führt aber zu einer irreversiblen Hemmung der Aromatase. Aufgrund der resultierenden Senkung des Estrogenblutspiegels wird 9 bei estrogenrezeptor-positivem Mammakarzinom eingesetzt. Für Exemestan (9) wurden verschiedene Synthesestrategien erprobt. Dabei anfallende Nebenprodukte wie 3-Pyrrolidinyl-estra-1,3,5(10)-trien-6,17-dion (18), 1-Chlor-4-methyl-estra-1,3,5(10)-trien-17-on (36), 6-Methoxymethyl-androsta-1,4-dien-3,17-dion (19) und 6-Chlormethyl-androsta-1,4-dien-3,17-dion (38) wurden isoliert und deren Struktur aufgeklärt. Exemestan (9) wurde in einer Michael-Addition mit Nitromethan zu 6-(2-Nitroethyl)-androsta-1,4-dien-3,17-dion (11) umgesetzt und dieses in einer Nef-Reaktion zu 6-(2-Oxoethyl)-androsta-1,4-dien-3,17-dion (12). Aus 12 wurde durch Hantzsch-Synthese Dimethyl-4-[(3,17-dioxoandrosta-1,4-dien-6-yl)methyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridindicarboxylat (13) dargestellt. 11, 12 und 13 erwiesen sich als etwas weniger potente Aromataseinhibitoren als 9. Um den Einfluss der Doppelbindung in Position 1 auf die Reaktivität der semicyclischen Doppelbindung gegenüber Nucleophilen einschätzen zu können, wurde das entsprechende 1,2-Dihydroderivat 6-Methylen-androst-4-en-3,17-dion (10) mit Nitromethan zu 6-(2-Nitroethyl)-androst-4-en-3,17-dion (32) umgesetzt. Als Nebenprodukt wurde Pyrido[3,4,5:4,5,6]androstan-3,17-dion (33) isoliert. 10 erwies sich als wesentlich reaktiver als 9. Aus 32 wurde 6-(2-Oxoethyl)-androst-4-en-3,17-dion (34) und daraus Dimethyl-4-[(3,17-dioxoandrost-4-en-6-yl)methyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridindicarboxylat (35) hergestellt. Exemestan (9) wurde durch einen Entwurf für eine Arzneibuch-Monographie sowie den zugehörigen Kommentar charakterisiert.Aromatase catalyzes the conversion of the androgens testosterone and androstenedione into the estrogens estradiol and estrone. Exemestane (6-methylen-androsta-1,4-diene-3,17-dione) (9) structurally resembles androstenedione, however, it leads to an irreversible inhibition of aromatase. Due to the resulting decrease of estrogen levels, 9 is applied in the therapy of estrogen-receptor-positive mamma carcinoma. Several strategies for the synthesis of exemestane (9) were investigated. The following by-products of these syntheses were isolated and structurally elucidated: 3-pyrrolidinyl-estra-1,3,5(10)-triene-6,17-dione (18), 1-chloro-4-methyl-estra-1,3,5(10)-triene-17-one (36), 6-methoxymethyl-androsta-1,4-diene-3,17-dione (19) and 6-chloromethyl-androsta-1,4-diene-3,17-dione (38). Exemestane (9) was subjected to Michael-addition with nitromethane to afford 6-(2-nitroethyl)-androsta-1,4-diene-3,17-dione (11), which yielded by Nef-reaction 6-(2-oxoethyl)-androsta-1,4-diene-3,17-dione (12). Dimethyl-4-[(3,17-dioxoandrosta-1,4-diene-6-yl)methyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridindicarboxylate (13) was obtained by Hantzsch-synthesis with 12. 11, 12 and 13 showed a reduced inhibitory potency towards aromatase compared to 9. To estimate the influence of the double bond in position 1 on the reactivity of the semicyclic double bond towards nucleophils, the corresponding 1,2-dihydro-compound 6-methylen-androst-4-ene-3,17-dione (10) was converted to 6-(2-nitroethyl)-androst-4-ene-3,17-dione (32) with nitromethane. Pyrido[3,4,5:4,5,6]androstan-3,17-dione (33) was obtained as by-product. 10 showed a higher reactivity than 9. 32 afforded 6-(2-oxoethyl)-androst-4-ene-3,17-dione (34), and 34 by Hantzsch-synthesis dimethyl-4-[(3,17-dioxoandrost-4-ene-6-yl)methyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridindicarboxylate (35). Exemestane (9) was characterized by the design of a monograph plus comment for the pharmacopoeia

Совершенствование организации рабочего места

Труд – это целесообразная деятельность людей, направленная на создание материальных и культурных ценностей, необходимых для удовлетворения потребностей каждого индивидуума и общества в целом. Люди, воздействуя на окружающую природную среду, изменяют ее, приспосабливая к своим потребностям, обеспечивают свое существование и создают условия для развития и прогресса общества. Роль труда в развитии человека и общества проявляется в том, что в процессе труда создаются не только материальные и духовные ценности, но развиваются сами работники, которые приобретают новые навыки, раскрывают свои способности. Объектом исследования бакалаврской работы является предприятие АО «Алмалыкский ГМК». Целью данной работы является разработка рекомендаций по совершенствованию рабочего места на предприятии АО «Алмалыкский ГМК». Структура бакалаврской работы состоит из введения, трех глав, заключения, списка использованной литературы. Актуальность темы состоит в том, что организация и нормирования труда на производстве являются важнейшими элементами экономики предприятия, посредством которых осуществляется взаимосвязь и взаимозависимость всех трудовых показателей со всеми другими показателями хозяйственной деятельности. Предложенные мероприятия могут успешно применяется в деятельности АО «Алмлалыкский ГМК». Работа выполнена на 74 страницах, содержит 13 таблиц, 7 рисунков, 4 приложения.Work - a purposeful activity of people, aimed at the creation of material and cultural values ​​necessary to meet the needs of every individual and society as a whole. People working on the environment, change it, adapting to their needs, ensure their existence and create conditions for the development and progress of society. The role of labor in the human and social development is manifested in the fact that in the process of labor are not only the material and spiritual values, but developing the workers themselves, who acquire new skills, show their abilities. The object of study Bachelor thesis is an enterprise of JSC "Almalyk MMC". The aim of this work is to develop recommendations for improving the workplace at the enterprise JSC "Almalyk MMC". Structure of bachelor work consists o

Wanderungstendenzen cyclischer, polycyclischer und methylverzweigter Alkylreste bei der Beckmann-Umlagerung

Die Wanderungstendenzen von polycyclischen Brückenkopfresten, Cycloalkylresten sowie , -und --verzweigten Alkylresten bei der Chapman-Variante der Beckmann-Umlagerung wurden bestimmt. Sie zeigen, daß die wandernde Gruppe im Übergangszustand 2 nicht Carbenium-Ionen-Charakter hat, sondern nach weitgehender Beibehaltung ihrer Geometrie eher einer Fünffach koordinierten Carboniumstruktur entspricht, die im Zuge der Umlagerungsreaktion vertikal stabilisiert4 werden kann

Les Cetotheriidae (Mammalia, Cetacea, Mysticeti) de la Formation Pisco (Miocène inférieur Pliocène inférieur) de la côte péruvienne. Relations phylogénétiques et affinités des Cetotheriidae

Les mysticètes à fanons comprennent généralement quatre familles actuelles et une famille fossile: les Cetotheriidae s.l. Dépourvus des synapomorphies des mysticètes actuels, ces fossiles sont un groupe paraphylétique peu étudié. La description de trois nouveaux taxons fossiles (Piscobalaena nana et deux nouveaux genres) de la Formation Pisco (Néogène, Pérou) a mis en évidence de nouveaux caractères morphologiques. Les Balaenopteridae ont une stratégie de nutrition très particulière à laquelle sont associés des caractères morphologiques du crâne et du dentaire. Six taxons fossiles présentent certains de ces caractères. Ils pourraient donc être phylogénétiquement proches des ces derniers et avoir utilisé la même stratégie nutritionnelle. L'analyse cladistique de 54 caractères (crâne, région auditive et dentaire) de 25 taxons suggère que huit des 15 taxons fossiles étudiés forment un clade : les Cetotheriidae s.s. Son groupe-frère comprend les taxons actuels et cinq fossiles.Baleen mysticetes traditionally comprise four living families and a fifth exclusively fossil family: the Cetotheriidae s.l.. New material (Piscobalaena nana and two new genera) from the Neogene Pisco Formation of Peru, yield new morphological data. Balaenopteridae have a peculiar feeding behaviour associated with some morphological characters of the skull and dentary. Six fossil taxa present similar morphologies. Thus they could be phylogenetically close to Balaenopteridae and could have used the same feeding behaviour. The cladistic analysis of 54 characters (skull, auditory area, dentary) of 25 taxa suggests that eight of the 15 studied Cetotheriidae s.l. constitute a clade: the Cetotheriidae s.s. Its sister-group includes the extant taxa and five fossil taxa.PARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF

Data on synthesis of oligomeric and polymeric poly(butylene adipate-co-butylene terephthalate) model substrates for the investigation of enzymatic hydrolysis

The aliphatic-aromatic copolyester poly(butylene adipate-co-butylene terephthalate) (PBAT), also known as ecoflex, contains adipic acid, 1,4-butanediol and terephthalic acid and is proven to be compostable [1–3]). We describe here data for the synthesis and analysis of poly(butylene adipate-co-butylene terephthalate variants with different adipic acid:terephatalic acid ratios and 6 oligomeric PBAT model substrates. Data for the synthesis of the following oligomeric model substrates are described: mono(4-hydroxybutyl) terephthalate (BTa), bis(4-(hexanoyloxy)butyl) terephthalate (HaBTaBHa), bis(4-(decanoyloxy)butyl) terephthalate (DaBTaBDa), bis(4-(tetradecanoyloxy)butyl) terephthalate (TdaBTaBTda), bis(4-hydroxyhexyl) terephthalate (HTaH) and bis(4-(benzoyloxy)butyl) terephthalate (BaBTaBBa). Polymeric PBAT variants were synthesized with adipic acid:terephatalic acid ratios of 100:0, 90:10, 80:20, 70:30, 60:40 and 50:50. These polymeric and oligomeric substances were used as ecoflex model substrates in enzymatic hydrolysis experiments in the article “Substrate specificities of cutinases on aliphatic-aromatic polyesters and on their model substrates” [4]. Keywords: Oligomer synthesis, Oligomer analysis, Polyester model substrate

Total Synthesis of Myxovirescin A₁

A convergent total synthesis of the antibiotic macrolide myxovirescin A1 (1) is described that is largely based on reagent- and catalyst-controlled transformations. This includes a highly regioselective Negishi reaction of dibromo-alkene 48 with an alkynylzinc reagent, and a palladium catalyzed alkyl-Suzuki coupling of the resulting enyne derivative 12 with the 9-BBN-adduct derived from alkene 61. The latter was obtained via an asymmetric hydrogenation of the chlorinated β-ketoester 49 and an anti-selective oxyallylation of the functionalized aldehyde 53 as the key steps. The preparation of the bis-borylated allyl-donor 57 used in the oxyallylation step, however, required careful optimization and led to important insights into the nature of the classical hydroborating agent “di(isopinocampheyl)borane (Ipc2BH)”. It was unambiguously shown by X-ray crystallography that in the solid state this compound is dimeric, but it is prone to undergo an essentially quantitative mono-deborylation when dissolved in CH2Cl2 or benzene; its composition in ethereal solvents is even more complex as evident from 11B NMR data. Product 71 derived from 12 and 61 was elaborated into the enyne–yne derivative 75, which served as the substrate for an exquisitely selective ring closing alkyne metathesis reaction (RCAM) catalyzed by the molybdenum tris-amido complex 20 activated in situ with CH2Cl2. The resulting cyclic enyne 76 was subjected to a ruthenium catalyzed trans-hydrosilylation/proto-desilylation tandem. Although [Cp*Ru(MeCN)6]PF1 had previously been recommended as catalyst of choice for trans-hydrosilylation reactions of internal alkynes, this complex failed to afford the desired product, whereas its sterically less hindered congener [CpRu(MeCN)3]PF6 permitted the reaction to be performed in appreciable yield, but at the expense of a lower stereoselectivity. AgF-mediated proto-desilylation of the isomeric silanes 79 and 80 followed by cleavage of the remaining acetal protecting groups afforded myxovirescin A1 and its hitherto unknown 14Z-isomer 81, respectively