Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

An Efficient Synthesis of Optically Pure (R)- and (S)-2-(aminomethyl)alanine ((R)- and (S)-ama) and (R)- and (S)-2-(aminomethyl)leucine ((R)- and (S)-aml)

An efficient synthesis of enantiomerically pure (R)- and (S)-2-(aminomethyl)alanine ((R)- and (S)-Ama) 1a and (R)- and (S)-2-(aminomethyl)leucine ((R)- and (S)-Aml) 1b is described (Schemes 1 and 2). Resolution of the racemic amino acids was achieved using L -phenylalanine cyclohexylamide ( 2 ) as chiral auxiliary. The free amino acids 1a, b were converted to the N^α-Boc,N^γ-Z-protected derivatives 11a, b (Scheme 3) ready for incorporation into peptides. Based on the three crystal structures of the diastereoisomeric peptides 8a, 8b , and 9b , the absolute configurations in both series were determined. β-Turn type-I geometries were observed for structures 8b and 9b , whereas 8a crystallized in an extended backbone conformation.     

Development of a gas chromatographic/mass spectrometric method to quantify R(-)-apomorphine, R(-)-apocodeine and R(-)-norapomorphine in human plasma and urine

A method was developed and validated for the analysis of R(-)-apomorphine, (R-)-apocodeine and R(-)-norapomorphine in human plasma and urine with N-propylnorapomorphine as internal standard using gas chromatography/mass spectrometry (GC/MS) and single-ion monitoring after a single liquid-liquid extraction and silylation of compounds. The quantification limits were 1 ng/ml for apomorphine and apocodeine and 25 ng/ml for norapomorphine. Calibration curves were linear, within the range 1-100 ng/ml. Variation in intraday and interday precision was below 10%. This method was applied to study apomorphine bioavailability in nine patients with Parkinson's disease before and after coadministration of a catechol-O-methyl transferase inhibitor.     

Aporphines 10. Approaches to the synthesis of 7-hydroxyaporphines : Stereoselective synthesis of (±)-10,11-dimethoxy-7-oxoaporphine, (±)-7-hydroxyaporphine and (±)-7-hydroxynoraporphine

A new method for the stereoselective synthesis of 7-hydroxyaporphine (3a) and 7-hydroxynoraporphine (3b) via the 4-oxazolin-2-one 20 as a protecting group has been developed. Pschorr cyclization of 20 and hydrolysis of the oxazoloaporphine 21 with trifluoroacetic acid led exclusively to the dehydronoraporphine 22. Reduction of 21 with LAH gave 3a and treatment of 21 with methyllithium gave 3b. The synthesis of 10,11-dimethoxy-7-oxoaporphine (2) involving a Reissert alkylation-Pschorr cyclization sequence has been achieved.     

Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile

(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.     

High-performance liquid chromatographic separation and electrochemical or spectrophotometric determination of R(-)N-n-propylnorapomorphine and R(-)10,11-methylenedioxy-N-n-propylnoraporphine in primate plasma

The dopamine receptor agonist R(-)N-n-propylnorapomorphine (NPA) and its proposed pro-drug R(-)10,11-methylenedioxy-N-n-propylnoraporphine (MDO-NPA) were isolated simultaneously from monkey plasma using a solid-phase extraction procedure. R(-)Apomorphine (APO) and R(-)10,11-methylenedioxyaporphine (MDO-APO) were added as internal standards, and separation and quantification were by high-performance liquid chromatography with electrochemical or ultraviolet detection of the free catechol and MDO compounds, respectively. The detection limits for NPA and MDO-NPA in plasma were 0.5 and 10 ng/ml and the coefficient of variation (S.D./mean) within assays and between days of assays for both drugs was 5.6% or less. Quantification of plasma levels of NPA and MDO-NPA was possible at ranges of 2-1000 and 40-5000 ng/ml, respectively, including concentrations found after intravenous administration of these agents.     

A novel strategy for the preparation of the injectable PET/CT radiopharmaceutical (-)-[11C]-(1R,2S)-meta-hydroxyephedrine ((-)-[11C]HED

Positron emission tomography (PET) had been applied in clinical early diagnosis of various tumors and other diseases. The methylated synthetic conditions of (-)-[¹¹C]-(1R,2S)-meta-hydroxyephedrine ((-)-[¹¹C]HED), considered as one of the most important radiopharmaceuticals for PET, were optimized through single factor and orthogonal design methods. Here, we reported an improved purification protocol. The radiochemical yields of the final product were over 45% (decay-corrected and based on [¹¹C]methyl iodide) (n?=?50). The radiochemical purities and chemical purities were over 99% (n?=?50) and 97% (n?=?50), respectively. The automatic radiosynthesis procedure of (-)-[¹¹C]HED with relatively high radiochemical yield was convenient and reliable.

     

Asymmetric Synthesis of (3R, 5R)-3-((tert-Butyldimethylsily)oxy)-5-((Z)-2-Bromovinyl)-Tetrahydro-Furan-2-one, an Intermediate for the Synthesis of Fostriecin

Fostriecin(CI-920) 11 a potential anticancer agent presently in phase I clinical trials at NCI is a novel phosphate ester produced by Streptomyces pulveraceus. Scheme 1 1 2 3 5 4 Synthesis of C10 epimer of compound 1 had been reported by Just G2. during the determination of its structure. On the basis of Just’s synthesis, a revised retro-asymmetric synthetic route of Fostriecin (scheme 1) was designed here of which compound 3 was synthesized from 5 with C3 in R configuration correspondi…     

Total synthesis of nominal (11S)- and (11R)-cyclocinamide A

The cyclocinamides possess a unique β(2)αβ(2)α 14-membered tetrapeptide core. The initially reported biological data and intriguing structure, which was without full stereochemical identification, necessitated synthesis of both nominal (all-S) cyclocinamide A and the 11R isomer. The completed synthesis is highlighted by the use of a (cyclo)asparagine-containing dipeptide as a turn inducing fragment. Due to inconsistencies in analytical data between natural and synthetic samples, a re-evaluation of the natural product stereochemistry appears necessary.     

Preparation of dimethyl (R)- and (S)-2-(2-aminophenyl)-2-hydroxyethylphosphonate from anthranilic acid

An efficient synthesis of both enantiomers of dimethyl δ-amino-β-hydroxyethylphosphonate 6 has been achieved starting from anthranilic acid, through the resolution of dimethyl (±)-2-(2-N,N-dibenzylaminophenyl)-2-hydroxyethylphosphonate 9 with (S)-O-methylmandelic acid. The absolute configuration of the enantiomers 9 was assigned by the Dale and Mosher approach using the extended Newman projections and molecular mechanics.     

Preparation of (R)-(+)-lithium lactate

Summary Optically pure (R)-(+)-lithium lactate (7) and its benzyl ether analogue (6a) were obtained from acetaldehyde usingEliel's 1,3-trans-oxathiane (1) as the chiral auxiliary for chromatographic separation.

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Herstellung von (R)-(+)-Lithiumlactat

Zusammenfassung Optisch reines (R)-(+)-Lithiumlactat (7) und sein Benzyletheranaloges (6a) wurden mittelsEliels 1,3-trans-Oxathian (1) als chiralem Hilfsstoff zur chromatographischen Trennung aus Acetaldehyd hergestellt.

     

A Convenient Preparation of (R)-7-(3-Benzothienylglycylamido)deacetoxycephalosopranic Acid

An efficient synthesis of (R)-7-(3-benzothienylamido)deacetoxy-cephalosporanic acid (1) is described beginning from (R)-alpha-aminobenzo[b]thiophene-3- acetic acid (2) and 7-amino-3-methyl-3-cephem-4-carboxylic acid (7-ADCA). Good yields were obtained and the procedure is amenable to multikilogram preparations.     

First application of tunable alkyl or aryl sulfinamides to the stereoselective synthesis of a chiral amine: asymmetric synthesis of (R)-didesmethylsibutramine ((R)-DDMS) using (R)-triethylmethylsulfinamide ((R)-TESA)

A highly diastereoselective addition of i-BuLi to a triethylmethylsulfinamide derived aldimine was used as the key step in the first asymmetric synthesis of (R)-didesmethylsibutramine, a metabolite of sibutramine for the potential treatment of CNS disorders. [reaction: see text]     

Improved Preparation of (R) and (S)-3-Aminoquinuclidine Dihydrochloride

An improved procedure for the synthesis of either (R) or (S)-3-aminoquinuclidine was developed. Key intermediate imine 2 was made in a one pot process using lithium oxide as the base and molecular sieves.