Unabhängige Synthese der violetten Farbstoffe aus 1,2-Naphthochinon-4-sulfonsäure und primären aliphatischen Aminen sowie eines Nebenproduktes

Independent Synthesis of the Violet Dyes and of a By-product Formed in the Reaction of 1,2-Naphthoquinone-4-sulfonic Acid with Primary Aliphatic Amines 4-Dimethylamino-1,2-naphthoquinone ( 8 ) and 2-dimethylamino-1,4-naphthoquinone ( 10 ) are O-methylated by methyl fluorosulfonate to form the stable iminium salts 9 and 11 . In an analogous way the 2-alkylamino-l,4-naphthoquinones 13 were transformed into the iminium salts 14 . These salts condense with 3-amino-4-hydroxynaphthalene-I-sulfonic acid ( 15 ) to give the violet 3-[(3-alkylamino-4-oxo-l-naphthyliden)amino]-4-hydroxynaphthalene-l-sulfonic acids 2 . The iminium salt 14c reacts with benzylamine to yield the vinylogous amidinium salt 19 , which is oxidised by silver oxide in pyridine to give the N-benzylidene-2-phenyl-5-naphth[2,1-d]oxazolamine 20 . Reduction of 20 with LiAIH₄, leads to the formation of N-benzyl-2-phenyl-5-naphth[2,l-d]oxazolamine ( 7 )     

Reaktionen an Heterocyclen mit 2-Acyl-2-propenon-Teilstruktur, 2. Mitt.1,2) Pyrido[2,3-d]pyrimidine aus 4-Oxo-4H-chromen-3-carboxaldehyden und 4-Aminouracilen

Reactions of Heterocycles Containing a 2-Acyl-2propenone Structure, II: Pyrido[2,3-d]pyrimidines from 4-oxo-4H-chromene-3-carbaldehydes and 4-Aminouraciles Depending on the solvent, 4-oxo-4H-chromene-3-carbaldehydes 1 react with 4-aminouraciles 2 , 6 and 10 to yield pyrido[2,3-d]pyrimidines of different structures. In dipolar aprotonic solvents the 6H-[l]benzopyrano[3,4-g]pyrido[2,3-d]pyrimidines 4 and 8 are formed. In hot glacial acetic acid the 6-(2-hydroxybenzoyl)pyrido[2,3-d]pyrimidines 5 , 9 and 14 are obtained.     

Beiträge zur Chemie des Pyridazinsystems, 29. Mitt. Synthese von 4-Arylpyrimido[4,5-d]pyridazinen aus (5-Amino-4-pyridazinyl)arylketonen

Pyridazine Chemistry XXIX: Synthesis of Pyrimido[4,5-d]pyridazines from (5-Amino-4-pyridazinyl)arylketones The pyrimido[4,5-d]pyridazin-2(1H)ones 4 and 6 are prepared in high yields from the amino ketones 1 or 5 . Procedures for the synthesis of the 4-arylpyrimido[4,5-d]pyridazines 8a, b, c via the imido esters 7a, b, c are described.     

Synthesis of three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor

Sodium ring‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from [¹⁴C]‐cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, [¹⁴C]‐4‐guanidinobenzoic acid, was prepared by coupling [¹⁴C]‐cyanamide with 4‐aminobenzoic acid. Sodium carboxyl‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1B) was synthesized from carboxyl‐[¹⁴C]‐4‐guanidinobenzoic acid in one step in a radiochemical yield of 35%. [D₄,¹⁵N]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (1C) was synthesized from [¹⁵N₂]‐cyanamide and [D₄]‐4‐aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β‐acyl glucuronide of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (14), was synthesized from D‐glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.     

2-Methoxypyridin und 2-Methoxychinolin als „inverse”︁ Dienophile gegenüber 3,6-Bis(trifluormethyl)-1,2,4,5-tetrazin

2-Methoxypyridine and 2-Methoxyquinoline as ?Inverse”? Dienophiles towards 3,6-Bis(trifluoromethyl)-1,2,4,5-tetrazine The title compounds 1 and 7 react with tetrazine 2 by two principally different pathways. On the one hand via, [4+2] cycloaddition followed by N₂-elimination and aromatization to yield the annulated pyridazines 3 and 8 , respectively, on the other hand by a novel kind of reaction to the condensed triazoles 5 and 10 .     

M+4 stable isotope labeling of levovirin and M+7 and carbon‐14 labeling of levovirin valinate pro‐drug

[M+4]‐labeled levovirin 5 (231 mg) was synthesized as an MS reference compound from [M+4] triazole ester 2 . [M+7]‐labeled levovirin valinate 6 (127 mg) was synthesized as a comparison MS reference compound from [M+6] triazole ester 3 . [¹⁴C]‐Levovirin 7 and [¹⁴C]‐levovirin valinate 8 were synthesized to support metabolism studies. The synthesis of 7 was accomplished in 33% overall yield (35.4 mCi, 57 mCi/mmol) from Ba¹⁴CO₃ and 8 was synthesized in 41% yield (12.5 mCi, 57 mCi/mmol) from 7 . An efficient metallation/carbonation reaction was developed to synthesize [¹⁴C]‐triazole ester 4 . Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of deuterium‐labelled 6‐[5‐(4‐amidinophenyl)furan‐2‐yl]nicotinamidine and N‐alkoxy‐6‐{5‐[4‐(N‐alkoxyamidino)phenyl]‐ furan‐2‐yl}‐nicotinamidines

6‐[5‐(4‐Amidinophenyl)furan‐2‐yl]nicotinamidine‐d₄ ( 5 ) was synthesized from 6‐[5‐(4‐cyanophenyl)furan‐2‐yl]nicotinonitrile‐d₄ ( 3 ), through the bis‐O‐acetoxy‐amidoxime followed by hydrogenation. Compound 3 was prepared from 6‐(furan‐2‐yl)‐nicotinonitrile by a Heck coupling reaction with 4‐bromobenzonitrile‐d₄, a product of selective cyanation reaction of 1,4‐dibromobenzene‐d₄ with Cu(1)CN. Deuterium‐labelled N‐methoxy‐6‐{5‐[4‐(N‐methoxy‐amidinophenyl]‐furan‐2‐yl}‐nicotinamidines were prepared via methylation of their respective amidoximes with dimethyl sulfate‐d₆ in aqueous sodium hydroxide in good yields. Copyright © 2004 John Wiley & Sons, Ltd.     

Dihydroisochinolinumlagerung, 32. Mitt.1) 4-Benzyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridine

Dihydroisoquinoline Rearrangement, XXXII: 4-Benzyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridines The synthesis of the title compounds 4a–4c was performed via the 4-benzylthieno[3,2-c]pyridines 2a–2c which were obtained by Grignard coupling or by Wittig alkylation of the chlorothienopyridine 1. Compounds 2a–2c were N-methylated to yield 3a–3c which in turn were reduced with LiAlH₄ to give the 4,5-dihydrothieno[3,2-c]pyridines 4a–4c. On treatment of 4a and 4b with dilute acids the disproportionation products 3a, 9a , and 3b, 9b were obtained with 10% yield. Treatment of 4c with dilute acid gave the disproportionation products 3c and 9c as well as the rearrangement product 8c with 30% yield. This shows that compounds other than 1,2-dihydroisoquinolines can rearrange in the same way as 1-benzyl-1,2-dihydroisoquinolines.     

Untersuchungen an 1,3-Dicarbonylverbindungen, 14. Mitt. 4-Oxo-4H-[1]benzofuro[3,2-b]pyrane und 4-Oxo-4H[1]benzothieno-[3,2-b]pyrane

1,3-Dicarbonyl Compounds, XIV: 4-Oxo-4H-[1]benzofuro[3,2-b]pyranes and 4-Oxo-4H-[1]benzothieno[3,2-b]pyranes The 1,3-dicarbonyl compounds 1 condense with dialkyl oxalates to form the 1,3,5,6-tetracarbonyl compounds 2 , which hydrolize under mildly alkaline conditions to give the ketocarboxylic acids 3 . Compounds 2 and 3 cyclize on heating with alcohols, saturated with HCl, to yield the alkyl 4-pyrone-2-carboxylates 4 . The acids 5 , obtained from 4 , decarboxylate on heating with quinoline/copper to give the heterocycles 6 . Compound 6b is also obtained from 1b by reaction with N,N-dimethylformamide dimethyl acetal (DMFDMA) and treatment with acid of the product 8b , whereas 1a and DMFDMA give the derivative 7a . Compounds 4 were characterized in the form of their amides 10 . The pyrylium salts 11 were obtained from 6 by reaction with dimethyl sulfate/HClO₄. Compounds 4 and 6 are converted to the thiocarbonyl compounds 12 and 13 by reaction with P₄S₁₀. Condensation of 2 with triethyl orthoformate/acetic anhydride yields the alkyl 4-pyrone-3-ketocarboxylates 14 . Compound 15b , formed by hydrolysis from 14b, afforded the 4-pyrone-3-carboxylic acid 16b by oxidative decarbonylation.     

Synthesis of isotopically labelled [14C]ZT‐1 (Debio‐9902), [d3]ZT‐1 and (−)‐[d3]huperzine A,a new generation of acetylcholinesterase inhibitors

A method has been developed for the synthesis of two isotopically labelled forms of a pro‐drug of the acetylcholinesterase inhibitor (?)‐huperzine A. These labelled compounds,[¹⁴C]ZT‐1 (Debio‐9902) and [d₃]ZT‐1, were used in clinical studies to evaluate a potential treatment for Alzheimer's disease. The pro‐drug [¹⁴C]ZT‐1 was isolated with a radiochemical purity of >98% and a gravimetric specific activity of 129 μCi/mg in a seven‐step synthesis starting from [U‐¹⁴C]phenol in 7% yield. Subsequently, the deuterium labelled target (?)‐[d₃]huperzine A was achieved in six steps with an overall yield of 15% and gave an isotopic distribution of d₂ (1.65% huperzine A) and d₃ (97.93% huperzine A) with a chemical purity of 98.5%. Condensation of the substrate (?)‐[d₃]huperzine A with 5‐chloro‐o‐vanillin gave the Schiff base [d₃]ZT‐1 in a chemical yield of 80%. Reduction of the Schiff base gave reduced‐[d₃]ZT‐1, which was converted into the hydrochloride salt with an isotopic distribution of d₂ (1.60%) and d₃ (98.02%). Copyright © 2011 John Wiley & Sons, Ltd.     

[4+1]-Cycloaddition von Benzylisonitril an cyclische Azadiensysteme des 1,2,4,5-Tetrazins und 1,2,4-Triazins

[4+1]-Cycloaddition of Benzyl Isonitrile with Cyclic Azadiene Systems of 1,2,4,5-Tetrazines and 1,2,4-Triazines Various donor substituted 1,2,4,5-tetrazines 1a-e and 1,2,4-triazines 7a,b react with benzyl isocyanide in a sequence of [4+1]-cycloaddition and [4+2]-cycloreversion steps to yield the unstable antiaromatic intermediates 4 and 8 , respectively. Subsequent [1,5-H]-shift leads to the corresponding azomethines. The pyrazoles 5a-e are isolable in high yields as stable crystalline compounds, whereas the pyrroles 9a and b are hydrolyzed by SiO₂/H₂O to yield benzaldehyde and the aminopyrroles 10a and 10b .     

Synthesis of d8‐geranyl diphosphate

Multiply labelled d₈‐geranyl diphosphate (3‐methyl‐7‐²H₃‐methyl‐[1,1,8,8,8]‐²H₅‐2E,6‐octadienyl diphosphate) was synthesised from geraniol in 8 steps. Geraniol was converted to [1,1]‐²H₂‐geraniol by a three step oxidation–reduction sequence in 38% yield. Selective epoxidation of [1,1]‐²H₂‐geranyl acetate gave 6,7‐epoxy‐[1,1]‐²H₂‐geranyl acetate, which, on oxidative cleavage of the epoxide and Wittig elaboration with d₆‐isopropyl triphenylphosphorane, gave d₈‐geraniol (14% yield) which was, in turn, converted to the title compound. Copyright © 2005 John Wiley & Sons, Ltd.     

Zur bromometrischen Bestimmung von Secobarbital-Natrium

Bromometric Assay of Secobarbital Sodium Secobarbital sodium ( 1a ) and the 1,3-bis-(4-nitrobenzyl)barbituric acid 2 react with KBrO₃ and KBr in acetic acid/HCl to yield the bromohydrines 3 and the dibromo compounds 5 . Dehydrobromination leads to the pyrano[2,3-d]pyrimidines 7 and 8 , respectively. The α-bromoketones 6 are obtained from 3 by oxidation with CrO₃. 6 cyclizes with thiourea to form the amino-thiazole 9 , while silver benzoate gives the activated ester 10 . In methanol secobarbital (1) reacts with Br₂ to yield the furo[2,3-d]pyrimidine 11 .     

Synthesis of Brostallicin (PNU‐166196A) Labelled with 2H and 14C

Brostallicin (PNU‐166196A), a DNA minor groove binder, has been labelled with ²H and ¹⁴C. The preparation of the deuterium specifically labelled [²H₄]brostallicin was achieved according to a nine‐step sequence starting from 1,2‐diamino[1,1,2,2‐²H₄]ethane (1) . [¹⁴C]Brostallicin was obtained via a four‐step procedure in 31% overall radiochemical yield starting from 1‐methyl‐4‐nitropyrrole‐2‐[¹⁴C]carboxylic acid (9) . Copyright © 2002 John Wiley & Sons, Ltd.     

Isochino[3,2-a]phthalazin-5,8-dione

Isoquino[3,2-a]phthalazine-5,8-diones Deoxybenzoin-2,2′-dicarboxylic acid (1) reacts with the hydrazines 4a-d to yield the phthalazinones 8a-d . Heating of 8a in acetic anhydride leads to the isoquino[3,2-a]phthalazinone 9a , which can also be prepared from 2 and 4a via the O, N-acetal 13 . From 1 and 1,2-dimethylhydrazine (4e) the spiro-compound 14 is formed.     

Radiosynthesis of [18F]ATPFU: a potential PET ligand for mTOR

Mammalian target of rapamycin (mTOR) plays a pivotal role in many aspects of cellular proliferation, and recent evidence suggests that an altered mTOR signaling pathway plays a central role in the pathogenesis of aging, tumor progression, neuropsychiatric, and major depressive disorder. Availability of a mTOR‐specific PET tracer will facilitate monitoring early response to treatment with mTOR inhibitors that are under clinical development. Towards this we have developed the radiosynthesis of [¹⁸F]1‐(4‐(4‐(8‐oxa‐3‐azabicyclo[3.2.1]octan‐3‐yl)‐1‐(2,2,2‐trifluoroethyl)‐1H‐pyrazolo[3,4‐d]pyrimidin‐6‐yl)phenyl)‐3‐(2‐fluoroethyl)urea [¹⁸F]ATPFU ([¹⁸F]1) as an mTOR PET ligand. Synthesis of reference 1 and the precursor for radiolabeling, 4‐(4‐8‐oxa‐3‐azabicyclo[3.2.1]‐octan‐3yl)‐1‐(2,2,2‐trifluoroethyl)‐1H‐pyrazolo[3,4‐d]pyrimidin‐6yl)aniline (10), were achieved from beta‐chloroaldehyde 3 in 4 and 5 steps, respectively, with an overall yield of 25–28%. [¹⁸F]Fluoroethylamine was prepared by heating N‐[2‐(toluene‐4‐sulfonyloxy)ethyl]phthalimide with [¹⁸F]fluoride ion in acetonitrile. [¹⁸F]1 was obtained by slow distillation under argon of [¹⁸F]FCH₂CH₂NH₂ into amine 10 that was pre‐treated with triphosgene at 0–5 °C. The total time required for the two‐step radiosynthesis including semi‐preparative HPLC purification was 90 min, and the overall radiochemical yield of [¹⁸F]1 for the process was 15 ± 5% based on [¹⁸F]fluoride ion (decay corrected). At the end of synthesis (EOS), the specific activity was 37–74 GBq/µmol (N = 6).     

Diuretika, 3. Mitt. 1-Carbocyclisch und heterocyclisch substituierte 4-Aminopyrazolo[3,4-d]pyrimidine

Diuretics, III: 4-Aminopyrazolo[3,4-d]pyrimidines with Carbocyclic or Heterocyclic Substituents at N-1 As analogues of the diuretically active 4,6-diamino-1-(2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidine, the 4-aminopyrazolo[3,4-d]pyrimidines 3a–g were prepared by condensation of the 5-amino-4-cyanopyrazoles 1a–g with formamide (2) .     

Synthesis and evaluation of in vitro antitubercular activity and antimicrobial activity of some novel 4H-chromeno[2,3-d]pyrimidine via 2-amino-4-phenyl-4H-chromene-3-carbonitriles

Novel 5-phenyl-1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dithiones, 5-phenyl-3,5-dihydro-4H-chromeno[2,3-d]pyrimidin-4-ones, 7-phenyl-7,9-dihydro-8H pyrimido[5′,4′:5,6]pyrano[3,2-h]quinolin-8-ones, and 4-amino-5-phenyl-1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2-thiones were synthesized form 2-amino-4-phenyl-4H-chromene-3-carbonitrile. The newly synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, Mass spectra, and Elemental analysis. The compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H ₃₇ Rv and antibacterial activity against Staphylococcus Aureus [ATCC-25923] and Streptococcus pyogenes [MTCC-443] as Gram-positive, Escherichia coli [ATCC-25922], and Pseudomonas aeruginosa [MTCC-441] as Gram-negative bacterial strains and antifungal activity against Aspergillus niger [MTCC-282]. Some of these derivatives exhibited pronounced antitubercular and antimicrobial activities.     

Condensed 1,2,4-Triazines,III

Alkylation of 3-mercaptophenanthreno[9,10-e]-1,2,4-triazine ( 1b ) yielded the S-alkyl derivatives 2 a-d . Amination of 1a afforded the 3-amino derivatives 3a-h . Reaction of 1a with hydrazine hydrate gave 3-hydrazinophenanthreno[9,10-e]-1,2,4-triazine ( 4 ) which underwent cyclisation with nitrous, formic or acetic acids giving the phenanthreno[9,10-e]-1,2,4-triazino[2,3-d]-1,2,3,4-tetrazole ( 5 ) and the phenanthreno[9,10e]-1,2,4-triazino[2,3-d]-3H-methyl-1,2,4-triazoles 6, 7 . Compound 4 also reacted with methyl [bis(dimethylmercapto)methylene]cyanoacetate, ethyl acetoacetate, ethoxymethylenemalononitrile, ethyl ethoxymethylencyanoacetate or acetyl acetone to yield the 3-(pyrazol-1-yl)-phenanthreno[9,10-e]-1,2,4-triazines 8–12 .     

Circadian rhythm of the B max of [3H]-imipramine binding in rabbit platelets

Summary [³H]-imipramine binding was measured in rabbit blood platelet membranes on a 24 h cycle. Animals were kept on a 14 h light (L) 10 h dark (D) schedule, and blood samples were collected at L + 2, L + 8, D + 2, D + 8 and L – 2 h on a following cycle. Significant differences were found for B_max values of [³H]-imipramine binding, with highest values during the dark phase and lowest during the light phase. No significant differences were found in K _d values. These results suggest the existence of a circadian rhythm for the B_max of [³H]-imipramine binding in blood platelets. Send offprint requests to S. Z. Langer