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1.
J Org Chem ; 81(8): 3447-56, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26991511

ABSTRACT

A practical and highly effective one-pot synthesis of versatile heteroaryl ketones directly from carboxylic acids and heteroaryl halides under mild conditions is reported. This method does not require derivatization of carboxylic acids (preparation of acid chlorides, Weinreb amides, etc.) or the use of any additives/catalysts. A wide substrate scope of carboxylic acids with high functional group tolerance has also been demonstrated. The results reveal that the presence of an α-nitrogen on the halide substrate greatly improves the desired ketone formation.

2.
J Labelled Comp Radiopharm ; 57(9): 574-8, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24992204

ABSTRACT

[(13) CD3 ]-TAK-459 (1A), an HSP90 inhibitor, was synthesized from [(13) CD3 ]-sodium methoxide in three steps in an overall yield of 29%. The key intermediate [(13) CD3 ]-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was synthesized in two steps from 2,6-dibromopyridine and stable isotope-labeled sodium methoxide. [(14) C]-TAK-459 (1B) was synthesized from [(14) C(U)]-guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [(14) C]-(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, was prepared by microwave-assisted condensation.


Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Carbon Radioisotopes/chemistry , Pyridines/chemistry , Pyrimidines/chemistry
3.
J Labelled Comp Radiopharm ; 56(9-10): 464-70, 2013.
Article in English | MEDLINE | ID: mdl-24285522

ABSTRACT

MLN9708 (ixazomib citrate) is an investigational, orally bioavailable proteasome inhibitor that is under development by Millennium in clinical studies in both hematologic and nonhematologic malignancies. The stable isotope-labeled MLN9708 was required for bio-analytical studies. [(13) C9 ]-MLN9708 (11) was synthesized in seven steps from the uniformly labeled [(13) C6 ]-1,4-dichlorobenzene (3) and [1-(13) C]-acetyl chloride. Because of the presence of two chlorine atoms and a boron atom, compound 6 was further reacted with [(13) C2 ]-glycine to provide an internal standard that is well separated from the parent compound during mass spectrometric analysis. The radiolabeled version was prepared to support metabolite profiling and whole body autoradiography studies in experimental animals. [(14) C]-MLN9708 (19) was synthesized in six steps from commercially available [(14) C]-barium carbonate. The key intermediate, [carboxyl-(14) C]-2,5-dichlorobenzoic acid (14), was prepared by selective lithiation of 1-bromo-2,5-dichlorobenzene (12) followed by carbonation with [(14) C]-barium carbonate. In preparation for a one-time human absorption, distribution, metabolism and excretion (ADME) study, the stability of [(14) C]-MLN9708 and its precursors were also evaluated.


Subject(s)
Boron Compounds/chemistry , Boron Compounds/chemical synthesis , Glycine/analogs & derivatives , Proteasome Inhibitors/chemistry , Proteasome Inhibitors/chemical synthesis , Carbon Isotopes/chemistry , Carbon Radioisotopes/chemistry , Chemistry Techniques, Synthetic , Glycine/chemical synthesis , Glycine/chemistry , Isotope Labeling
4.
Org Lett ; 14(10): 2626-9, 2012 May 18.
Article in English | MEDLINE | ID: mdl-22571722

ABSTRACT

A convenient and efficient procedure is described for the sulfamoylation of alcohols using N-(tert-butoxycarbonyl)-N-[(triethylenediammonium)sulfonyl]azanide (1). The ambient temperature stable reagent 1 reacts with phenols as well as primary and secondary alcohols to give high to modest yields. The relative reaction rate of substrates was determined (primary > phenol > secondary ≫ tertiary). The reagent's utility as a selective sulfamoylation reagent with polyols is also demonstrated.


Subject(s)
Alcohols/chemistry , Sulfones/chemistry , Amines , Indicators and Reagents , Molecular Structure , Phenols
5.
J Am Chem Soc ; 128(17): 5646-7, 2006 May 03.
Article in English | MEDLINE | ID: mdl-16637626

ABSTRACT

The first syntheses of any members of the naturally occurring pyrazolo[4,3-e][1,2,4]triazine family are reported, verifying the structures of nostocine A and fluviol A, and leading to the revision of the structure of pseudoiodinine. The revised structure of pseudoiodinine was also established by total synthesis.

6.
Org Lett ; 7(12): 2449-51, 2005 Jun 09.
Article in English | MEDLINE | ID: mdl-15932220

ABSTRACT

[reaction: see text] The first syntheses of the pyridazinoindazolium alkaloids nigellicine and nigeglanine hydrobromide via a common intermediate are described. Ortho-lithiation/acylation and the direct amination of an isatin ring system are the key steps in the synthesis.


Subject(s)
Alkaloids/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Indazoles/chemical synthesis , Molecular Structure , Nigella/chemistry
7.
Org Biomol Chem ; 3(4): 581-3, 2005 Feb 21.
Article in English | MEDLINE | ID: mdl-15703791

ABSTRACT

The X-ray crystal structure and photophysical properties of 1,6,7,12,13,18,19,24-octamethylacenaphthyleno[b,l]tetraphenylene, which has been synthesized via a Diels-Alder reaction of 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene and 6,7-dihydro-6-hydroxy-7,9-dimethyl-8H-cyclopenta[a]acenaphthylene-8-one, are reported.

8.
Org Biomol Chem ; 3(3): 407-13, 2005 Feb 07.
Article in English | MEDLINE | ID: mdl-15678177

ABSTRACT

The synthesis of three new silver(I) complexes with corannulene is reported. In the crystal these complexes form extended networks of Ag(+) ions, corannulene nuclei, and counterions, similar to the networks reported for Ag(+) with other polynuclear aromatic hydrocarbons (PAHs). The preferred Ag(+)-arene interaction is compared with the model developed by Kochi. The crystal motifs can be described by a classification scheme analogous to that developed by Etter for hydrogen-bonded networks in solids. The effect of counterion variation (ClO(4)(-), O(3)SCF(3)(-), BF(4)(-)) is noted to be substantial. Thus, although one can categorize the various networks, it is hard to predict an expected packing pattern on the basis of preferred binding in the metal/organic complex alone.

9.
Org Lett ; 6(26): 4953-6, 2004 Dec 23.
Article in English | MEDLINE | ID: mdl-15606108

ABSTRACT

[reaction: see text] An enantiospecific synthesis of the AB fragment of lactonamycin (5) is achieved in eight steps from dimethyl D-tartrate. Ester enolate chemistry features prominently in the sequence.


Subject(s)
Indoles/chemical synthesis , Indoles/chemistry , Molecular Conformation , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Stereoisomerism
10.
Org Lett ; 5(5): 713-6, 2003 Mar 06.
Article in English | MEDLINE | ID: mdl-12605497

ABSTRACT

Alkyl, aryl, and alkynyl as well as heteroatom derivatives of sym-pentasubstituted corannulenes have been synthesized from sym-pentachlorocorannulene. These units form potential building blocks for future work on superstructures based on corannulene. Absorption/emission properties follow expected trends from the parent 1. sym-Pentasubstitution gives rise to variations in the chemical dynamics of bowl inversion. van der Waals attraction is cited to explain an anomalously high barrier to bowl inversion in 10.

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