[Motor and Sensory Blockade by Combined Spinal-Epidural Anesthesia for Cesarean Delivery].

BACKGROUND: We compared three combined spinal-epidural anesthesia (CSEA) techniques for cesarean delivery. Hypotension, nausea and vomiting are main problems produced by coonventional intrathecal doses. These problems were our secondary observations. Our primary observations were motor recovery and intraoperative pain. METHODS: Sixty patients were randomly allocated to one of the 3 groups (n = 20 per group). Group B (conventional dose): received intrathecally 0.5% hyperbaric bupivacaine (10 mg; < 160 cm in height 11 mg ; ≥ 160 cm in height) and epidural catheter at T12-L1. Group F (low-dose and addition of fentanyl) : received intrathecally 0.5% hyperbaric bupivacaine (70% of group B) with fentanyl 20 mg and epidural catheter at T12-L1. Group E (low-dose and epidural volume extension : EVE) : received intrathecally 0.5% hyperbaric bupivacaine (70% of group B) and epidural catheter at L3-4, through which 10 ml saline was injected 3 minutes after intrathecal injection. RESULTS: Group F and E demonstrated faster motor recovery than group B. More patients in group E than those in group B and F complained of intraoperative pain. There was no incidence of hypotension, nausea and vomiting. CONCLUSIONS: Group F and group E demonstrated similar fast motor recovery, but the former caused less intraoperative pain than the latter. Because this is an observational study, comparison of techniques such as addition of fentanyl, EVE, needs a compatative study.

Practical synthesis of a neuropeptide Y antagonist via stereoselective addition to a ketene.

[Reaction: see text]. The synthesis of neuropeptide Y antagonist 1, currently under clinical investigation for the treatment of obesity, is described. The convergent synthesis from trans-spirolactone carboxylic acid intermediate 2a and aminopyrazole 3 is predicated on a stereoselective route to the former. The coupling reaction of ethyl 4-oxocyclohexanecarboxylate (10a) with lithiated isonicotinamide 11 was investigated in detail, but even optimized conditions only provided a 45:55 ratio of trans:cis isomers (12a:12b). While selective crystallization schemes were developed to isolate the thermodynamically less stable trans isomer 2a, improved stereocontrol was subsequentially achieved by the application of ketene chemistry. The ketene formation and quench was investigated under a variety of conditions aimed at maximizing the trans:cis ratio. Reacting a mixture of carboxylic acids 2a and 2b with POCl3 in THF, followed by concomitant addition of tert-butyl alcohol in the presence of TMEDA at 35 degrees C provided a 4:1 ratio of trans:cis tert-butyl esters (18a:18b) via in situ ketene formation. Ester hydrolysis, followed by selective crystallization of undesired 2b as the HCl salt, led to isolation of 2a in 47% overall yield. Aminopyrazole intermediate 3 was synthesized via the condensation reaction of 2-fluorophenylhydrazine hydrochloride (4a) with acrylonitrile derivative 5 in 65-70% yield. Coupling of advanced intermediates 2a and 3b via activation with thionyl chloride gave a 92% yield of 1.

Scalable enantioselective processes for chiral pharmaceutical intermediates.

The importance and practicality of asymmetric synthesis to obtain enantiomerically pure drug substances has been fully recognized by process chemists of the pharmaceutical industry. Catalytic enantioselective processes would be particularly advantageous, compared to processes requiring stoichiometric amounts of chiral initiators, and would also be of interest from an environmental perspective. Since the commercialization of the Monsanto process for the manufacturing of L-DOPA in the early 1970s, catalytic asymmetric reactions have often been utilized in the commercial production of active pharmaceutical ingredients. This review will focus on recent advances in the development of scalable enantioselective processes for chiral pharmaceutical intermediates.

Practical synthesis of wybutosine, the hypermodified nucleoside of yeast phenylalanine transfer ribonucleic acid.

An improved synthesis of 3-beta-D-ribofuranosylwybutine (2) has been achieved by the Wittig reaction between 4,6-dimethyl-9-oxo-3-[2,3,5-tris-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-4,9-dihydro-3H-imidazo[1,2-a]-purine-7-carbaldehyde (8) and the phosphorane derived from (R)-2-[(methoxycarbonyl)amino]-3-(triphenylphosphonio)propanoate (9), followed successively by methylation, hydrogenation, and deprotection. On the other hand, the minor nucleoside wybutosine of yeast tRNA(Phe) was isolated on a scale of 80 microg by partial digestion of unfractionated tRNA (1 g) with nuclease P1, followed successively by reversed-phase column chromatography, complete digestion with nuclease P1/alkaline phosphatase, and reversed-phase HPLC. Comparison of this nucleoside with 2 has unambiguously established that the structure of wybutosine is (alphaS)-alpha-[(methoxycarbonyl)-amino]-4,6-dimethyl-9-oxo-3-beta-D-ribofuranosyl-4,9-dihydro-3H-imidazo[1,2-a]purine-7-butanoic acid methyl ester (2).

Efficient synthesis and hydrolysis of cyclic oxalate esters of glycols.

Based on the mechanism postulated for the formation of the cyclic carbonates 3 in the reactions of glycols 1 with oxalyl chloride in the presence of triethylamine, we present here three efficient syntheses of the cyclic oxalates 2 of various glycols 1 by controlling the formation of 3: replacement of the base by pyridine markedly diminishes yields of 3 in all reactions, realizing dramatic reversals of the product ratios in the reactions with the (R*,R*)-compounds 1g-i,q,r and pinacol (1k); although considerable amounts of the oxalate polymers are formed in the reactions with some (R*,S*)-glycols, this drawback can be removed by the use of 2,4,6-collidine instead of pyridine; 1,1'-oxalyldiimidazole is useful for the synthesis of two selected cyclic oxalates 2e,f. The cyclic oxalates 2 other than trisubstituted and tetrasubstituted ones were found to be very reactive: kinetic studies on the hydrolysis of 1,4-dioxane-2,3-dione (2a) as well as its mono- and some selected 5,6-disubstituted derivatives 2 have revealed that they undergo hydrolysis 260-1500 times more rapidly than diethyl oxalate (12) in acetate buffer-acetonitrile (pH 5.69) at 25 degrees C. Although the cyclic oxalate 21 from cis-1,2-cyclopentanediol (11) was 1.5 times more reactive than 2a, it has been shown with other substrates that increasing number of the alkyl substituents decreases the rate of hydrolysis. On the contrary, the phenyl group was found to have somewhat accelerative effect.

Reactions of oxalyl chloride with 1,2-cycloalkanediols in the presence of triethylamine.

The relationship between the product patterns and the configurations of 1,2-cycloheptane- and 1,2-cyclooctanediols 9 in the cyclocondensations with oxalyl chloride in the presence of triethylamine at 0 degrees C has been shown analogous to that obtained for 1,2-disubstituted acyclic ethylene glycols 1: cis-1,2-cyclooctanediol (9f) produced the cyclic oxalate 14f as the major product, while trans-1,2-cycloheptanediol (9e) and trans-1,2-cyclooctanediol (9g) formed the cyclic carbonates 12e, g as the major products. On the other hand, the cyclic oxalates 14a-d were formed as the major products from 1,2-cyclopentane- and 1,2-cyclohexanediols regardless of the configuration. These results can be accounted for by assuming the boat-like transition states for cyclizations of the half esters of comparatively rigid five- and six-membered diols 9a--d. The cyclic oxalates 14a, c may be directly formed through the resulting tetrahedral intermediates from cis-diols (9a,c), and the cyclic carbonates 12a,c as the minor products after ring inversion of the tetrahedral intermediates. The tetrahedral intermediates from the trans-isomers 9b, d cannot undergo ring inversion, producing no traces of the cyclic carbonates 12b, d.

Enantioselective Ring Opening of Epoxides with 4-Methoxyphenol Catalyzed by Gallium Heterobimetallic Complexes: An Efficient Method for the Synthesis of Optically Active 1,2-Diol Monoethers.

Useful chiral building blocks such as 1,2-diols can be obtained by the enantioselective ring opening of achiral epoxides with oxygen nucleophiles. The ring opening is carried out effectively (up to 94 % ee) with 4-methoxyphenol and catalytic amounts of gallium complexes. The novel complex GaSO 1 displays a particularly high catalytic activity.