Synthesis of Repaglinide Congeners

This report describes a synthesis of two potent impurities of repaglinide, benzyl repaglinide 1 and repaglinide isomer 2, from commercially available raw materials: 2-fluoro benzonitrile, (S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butylamine (5), and 3-ethoxy-[4-(ethoxycarbonyl)phenyl]acetic acid (7). These impurities are the crucial components in determining the quality of the drug substance, repaglinide, during its manufacturing.     

Synthesis of Valganciclovir Hydrochloride Congeners

Valganciclovir hydrochloride (1) is used for the treatment of cytomegalovirus (CMV) retinitis in patients with weakened immune systems. Valganciclovir hydrochloride is a hydrochloride salt of L-valyl ester of ganciclovir (2) that exists as a mixture of two diastereomers. According to the U.S. Food and Drug Administration specifications, the diastereomeric ratio of valganciclovir hydrochloride 1 should be maintained in the range 55:45 to 45:55. According to the U.S. Food and Drug Administration specifications, the diastereomeric ratio of valganciclovir hydrochloride 1 should be maintained in the range 55:45 to 45:55. During the process development of valganciclovir hydrochloride, six related substances (impurities) were observed along with the final active pharmaceutical ingredient. Among these six impurities, ganciclovir (2) and guanine (3) are the key starting materials and degraded impurities of ganciclovir, respectively. The remaining four impurities were identified as isovalganciclovir hydrochloride (4), methoxymethylguanine (5), O-acetoxy ganciclovir (6), and isovalarylganciclovir (7). The present work describes the synthesis and characterization of these four impurities.     

立体脱氧合成环十六-9-烯内酯

以环十六-9,10-二羟基内酯为原料,经缩醛成环和立体脱氧合成环十六-9-烯内酯(2),其结构经1H NMR,13C NMR,IR和ESI-MS确证。抑菌活性和热性质研究结果表明:2在不同气氛中难以发生热裂解行为;2具有较好的抑菌作用,对白色念珠菌和宋内氏志贺氏菌的最小抑制浓度分别为992μM和62μM。     

Stereospecific Synthesis of Methyl Vinyl Ketones

A stereospecific synthesis of enones 3 by coupling reaction of α-acetoxy alkyl methyl vinyl ketones 2 and Gilman or Grignard reagents in the presence of a catalytic amount of copper (I) salt at low temperature, is described.     

Stereospecific Synthesis of D-Glycero-D-ido-oct-2-ulose

Summary.  D-Glycero-D-gulo-heptose reacted with 2,2-dimethoxypropane to give its 2,3:6,7-di-O-isopropylidene derivative. Its base-catalyzed addition to formaldehyde resulted in the formation of 2,3:6,7-di-O-isopropylidene-2-C-(hydroxymethyl)-D-glycero-D-gulo-heptofuranose. After acid hydrolysis of this aldolization product, a new branched-chain aldose, 2-C-(hydroxymethyl)-D-glycero-D-gulo-heptose, was obtained, which was stereospecifically rearranged under the catalytic action of molybdic acid to D-glycero-D-ido-oct-2-ulose. Received October 17, 2000. Accepted December 4, 2000     

The Synthesis of Aromatic Hydrazones as Nitrogen-Containing Prostaglandin Congeners

Severalnitrogen-containingprostaglandincongeners,suchasAHl9437[I]andSQ29548II',werereportedt0beexhibitingpotentactivitiesontissuesclassifiedascontainingTX-sensitivereceptors(TP).Theseledustopreparetheimp0rtantintermediatesIIIbyusingsubstitutedanilinesthroughthenucle0philicoxiranering0peningreacti0n0f2,3-ep0xylbicyclo[3.2.O]hept-6-one'.Inthisarticle,wereport0nthesynthesis0faromatichydraz0nesIVasnitrogen-c0ntainingprostaglandinc0ngenersfromdifferentar0matichydrazinesandIIItosearchforTP-r…     

Stereospecific Olefin Synthesis via Lithium Vinylcuprates

The conjugate addition of cis- or trans-1-alkenyl-cuprolithium complexes (R? CH?CH? )₂CuLi · X_n

1 R ? alkyl, X ? ligands such as ether, tetrahydrofuran, (CH₃O)₃P and (n-Bu)₃P. Physical studies to determine the structure of these copper reagents are in progress, see footnote ²⁰ of reference [1].

to α, β-unsaturated carbonyl compounds was found to occur with high retention of double bond geometry, affording isomerically pure cis- or trans-γ, δ-ethylenic carbonyl compounds. The same 1-alkenylcuprates also react stereospecifically with alkyl halides to give isomerically pure cis- or trans-olefins.     

A Stereospecific Synthesis of Cis-3-Substituted-2, 2-Dimethylcyclopropane-L-Carboxylates

A stereospecific synthesis of cis-3-substituted-2, 2-dimethylcyclopropane-1-carboxylates based on the cyclization of 5-bromolactone 2 to give bicyclic lactone 3 is described.     

基于同一天然手性源(4R)-羟基脯氨酸的(2S,4S)/(2S,4R)-4-氟谷氨酸的立体专一性合成

基于同一天然手性源(4R)-羟基脯氨酸,通过Mitsunobo反应、全氟丁基磺酰氟作用下的氟化反应以及NaIO4/RuO2作用下的氧化反应,立体专一性地合成了(2S,4S)/(2S,4R)-4-氟谷氨酸.     

Stereospecific Synthesis of Carbanucleotides Designed for Antisense Methodology

A short stereospecific synthesis of the carbocyclic 2′‐deoxynucleoside analogues 36 and 37 (Schemes 2 and 5) and 45 and 46 (Schemes 2 and 6) starting from optically active 8,9,10‐trinorborn‐5‐en‐2‐one ( 1 ) is described. As two functional groups capable to react with each other are present in the same molecule of the synthetic carbanucleosides, the latter can form polymers similar to oligonucleotides.     

A New Two-Step Stereospecific Synthesis of Glycidic Spiroacetals

ABSTRACT

The spiroacetal moiety has received much attention in recent years owing to its occurence in several biologically important natural products.¹ In that field, the antibiotics avermectins,² milbemycins³ and papulacandins⁴ are of particular interest to us because a carbohydrate precursor could be employed for their syntheses.^5-7 other glycidic spiroacetals were obtained by photocarbocyclization of 2-carbophenyl-β-D-glucopyranosides.⁸     

Determination of Benzidine and its Congeners by Liquid Chromatography with Electrochemical Detection

High performance liquid chromatography coupled with electrochemical detection (HPLC-EC) method has been developed for the determination of benzidine and its related congeners in wastewater at the low ng/mL level. With a µ-Bondapak C₁₈ column, 53% acetonitrile (pH 4.7), and electrochemical detection at +1.0 V applied potential, the detection limits range from 3 ng/mL for benzidine to 10 ng/mL for 3,3′-dichlorobenzidine, assuming a 100 µL injection. The detection limits can be further lowered to the sub-ng/mL level by incorporating a short precolumn into the HPLC system for on-line sample enrichment. Recoveries are generally greater than 80% — except for benzidine and 3,3′-diaminobenzidine which give 50–70% recoveries. Industrial wastewater samples from a coke-plant and a plant producing 3,3′-dichlorobenzidine based dyes were successfully studied via this method.     

A Convenient and Stereospecific Synthesis of (Z)-Benzylidenephthalides

Several 3-benzylidenephthalides have been isolated from natural sources1-2. Some of them are known to possess useful biological activity1 and are also valuable intermediates3 for the synthesis of naturally occurring biologically active compound. Most of the natural 3-benzylidenephthalides exist in the (Z)-configuration. Synthe-tic methods for construction of a 3-benzylidene-phthalide skeleton have been developed4. Some of these methods for synthesizing highly oxygen-functionalized compound…     

Stereospecific Grignard-Activated Solid Phase Synthesis of DNA Methylphosphonate Dimers

Stereoregular R(p) or S(p) DNA methylphosphonate dimers have been synthesized on a solid phase support. A deprotected 5'-hydroxyl-N(2)-isobutanoyldeoxyguanosine 3'-O-succinate coupled to high-loaded polyethylene glycol (PEG) coated polystyrene beads (HLP) was activated with a Grignard reagent, t-BuMgCl. After activation was complete, a pure diastereoisomer of 5'-(dimethoxytrityl) N-benzoyldeoxynucleoside 3'-(p-nitrophenyl methylphosphonate) p-nitrophenyl ester (R(p) or S(p)) was added. Coupling of the activated 5'-hydroxyl to the 3'-methylphosphonate ensued, releasing nitrophenol, yielding the R(p) or S(p) dimer, respectively. The dimers were then cleaved from the solid support, deprotected, and purified, yielding methylphosphonate DNA dimers of defined stereochemistry.