Upjohn procedure

Diels-AUer reactions. This diene can serve as a precursor to the highly oxygenated cyclohexane derivative shikimic acid (3), as shown in Scheme 1. Oxidative desilylation of the Diels-Alder adduct 2 could not be effected with peracids, but was effected by cis-dihydroxylation (Upjohn procedure, 7, 256-257) followed by p-elimination of (CH3)3SiOH with TsOH. Introduction of the 4a,5P diol system was effected indirectly from the 4a,5a-epoxide in several steps, since direct hydrolysis of the epoxide resulted in a mixture of three triols.1... 

Osmium tetroxide is very expensive and very toxic which made using it quite unattractive. For a long time, many people who used osmium tetroxide to convert olefins to diols—and this was long before enantioselective dihydroxylations came on the scene—used the Upjohn procedure.20 This process used catalytic amounts of osmium tetroxide, NMO (/V-methylmorpholine /V-oxidc) 87 as the stoichiometric oxidant, and one solvent phase. The solvent was water, acetone and tert-butyl alcohol. The osmate ester 86 was hydrolysed under these conditions and the osmium (VI) species was reoxidised to 0s04 by NMO. 

One of the problems encountered in the development of the AD reaction was a second cycle.23 The first cycle is the same as the cycle we saw in the Upjohn procedure with one modification. It is possible for the osmium in the osmate (VI) ester to become oxidised before hydrolysis to form an osmate (VIII) ester. If this species simply hydrolyses to diol and 0s04 then there is no problem but otherwise this is where the trouble starts. In the second cycle the osmate (VIII) ester reacts with another olefin instead of being hydrolysed. It does so with low enantioselectivity (and sometimes in the opposite sense to the first cycle) which results in the poorer enantiopurity of the product (step D rather than step C below). One way round this is to keep the olefin concentration as low as possible which can be done by adding the olefin slowly.22,23 Although slow olefin addition resulted in a profound improvement in enantiomeric excess, it was inconvenient and no way near as effective as the alternative which was to alter the conditions. The use of two phases makes it impossible for the second cycle to occur.19,24... 

As with permanganate oxidations, a-hydroxy ketones can be formed as side products. In some cases, structural features make the osmium complex relatively unstable, and in an aqueous medium it can react with water to give a hydroxy-hydrate, which is then converted to an a-keto alcohol. Sharpless et al. developed a procedure that used tert-butyl hydroperoxide with a catalytic amount of osmium tetroxide,367 in the presence of tetraethylammonium hydroxide (EtqN" " OH ). The procedure gave improved yields of the cis-diol and a little a-hydroxyketone, as shown in the conversion of oct-(4 )-ene to a mixture of 258 and 259 in 73% yield. This method is more reliable for oxidation of tri- and tetrasubstituted alkenes than the Upjohn procedure. The reaction was not suitable for base sensitive alkenes, but later work showed that changing the solvent to acetone allowed the use of tetraethylammonium acetate (Et4NOAc) 68 for the hydroxylation of sensitive alkenes such as ethyl crotonate. 

Since the publication of the Upjohn procedure in 1976, the use of N-methylmorpho-line N-oxide (NMO) based oxidants has become one of the standard methods for osmium-catalyzed dihydroxylations. However, NMO has not been fully appreciated in the asymmetric dihydroxylation for a long time since it was difficult to obtain high enantiomeric excess (ee). This drawback was significantly improved by slow addition of the alkene to the aqueous tert-BuOH reaction mixture, in which 97% ee was achieved with styrene [15]. 

Ever since the Upjohn procedure was pubhshed in 1976 the N-methyhnorpholine N-oxide-based procedure has become one of the standard methods for osmium-catalyzed dihydroxylations. However, in the asymmetric dihydroxylation NMO has not... 

A iD-Corticoids have been important intermediates since it was shown ° that substitution at C-9 enhances anti-inflammatory activity. These olefins are usually obtained from 11a- or 11)5-alcohols, and consequently several refined methods have been devised for effecting this dehydration. It is desirable that such methods be compatible with the presence of A" -3-ketone and 17-hydroxy functions. The first direct procedure for which high yields were claimed was described in a patent issued to Upjohn. According to this method, the alcohol (11a or )5) is treated first with A-bromoacetamide in pyridine, then with sulfur dioxide. Recently it has been claimed " that the A-haloamide/sulfur dioxide method gives results superior to other methods, although the methanesulfonyl chloride/sulfur dioxide procedure (see below) apparently was not compared (see also ref. 94). 

Scheme 6. Corey s synthesis of gibberellic acid GA3 (22) employing the Upjohn catalytic dihydroxylation procedure.

Sharpless stoichiometric asymmetric dihydroxylation of alkenes (AD) was converted into a catalytic reaction several years later when it was combined with the procedure of Upjohn involving reoxidation of the metal catalyst with the use of N-oxides [24] (N-methylmorpholine N-oxide). Reported turnover numbers were in the order of 200 (but can be raised to 50,000) and the e.e. for /rara-stilbene exceeded 95% (after isolation 88%). When dihydriquinidine (vide infra) was used the opposite enantiomer was obtained, again showing that quinine and quinidine react like a pair of enantiomers, rather than diastereomers. 

Before the formation of Pharmacia through the merger of Pharmacia Upjohn with Monsanto-Searle in 2000, each company had its own approaches to augment and diversify their compound collections, and these approaches set the stage for the procedure implemented at Pharmacia. Thus, it was felt that a brief description of the historical background to the present work would be informative and would afford additional insights that bear directly on the development of the compound acquisition strategy described here. 

Describes a procedure based on the Upjohn Mini-Comer Test. 

As has been described above, HA is an essential functional component of almost all tissues in the vertebrate organism. Thus, various animal tissues - e.g. rooster combs, shark skin, bovine eyeballs - have been used as sources of isolation and production of high molar mass HAs. Since in the biological materials HA is usually present in a complex linked to other biopolymers, several separation procedures have to be applied in order to obtain a pure compound, such as protease digestion, HA ion-pair precipitation (with e.g. cetylpyridinium chloride), membrane ultrafiltration, HA non-solvent precipitation and/or lyophilization [135,136]. The mean molar mass of the commercially available extractive HA preparations obtained from animal tissues is mostly in the range from several hundred thousands Da up to approximately 2.5 MDa. To date, the demand for HA materials approved for applications in human medicine has been satisfied by high molar mass HAs prepared from the rooster combs. For example, Healon (Pharmacia Upjohn, Inc., Peapack, NJ, USA) - used in viscosurgery at eye implant insertion - has a mean HA molar mass of about 2.5 MDa. 

The materials employed in these formulations consisted of bitolylene diisocyanate (3,3 -dimethyl-4,4 -biphenylene diisocyanate, 136T Upjohn Co.) referred to as T0DI, a polyether diol (tetramethyleneoxide polyol, Polymeg 2000, Quaker Oats Co.), a polyester diol (caprolactone polyol, PCP-200, Union Carbide Corp.) and a chain extender, 1,4-butanedio1 (Aldrich Chemical Co.). The formulations were prepared by a two-step procedure. In... 

Figure 4. Anticoagulant activity of individual heparin chains of beef-lung heparin. Chains were separated by electrophoresis of Upjohn beef-lung heparin Lot 517-042 with LKB carrier ampholine batch 18. The apparent molecular weights were obtained from electrophoresis in acrylamide by the technique of Hilborn and Anastassiadis (10). The anticoagulant activity was determined by the USP procedure comparing the individual fraction with the original heparin. The quantity was estimated by optical density of toluidine blue-stained band on gel. (2)...

Reference standards. Pirlimycin was obtained as an Upjohn Control Reference Standard of purity >99% as the hydrochloride hydrate. Pirlimycin sulfoxide was prepared from the treatment of pirlimycin with hydrogen peroxide followed by recrystallization. Samples of pirlimycin adenylate and pirlimycin sulfoxide adenylate were prepared by the procedures described by Argoudelis et al (6). 

Pharmacia Upjohn developed a practical synthesis toward the anticancer agent Irinotecan (Camptosar, 24), which involved an enzymatic resolution step to provide the strategic intermediate 23 (Scheme 7) [65,66]. Lactone 23 could be produced by internal esterification of oxidized (S)-diol 21, which in turn was obtained by biocatalytic resolution of mc-21. An asymmetric acetylation was achieved with isopropenyl acetate catalyzed by Amano PS-30 Pseudomonas cepacia) lipase immobilized on Celite and could be driven to 60% conversion. (S)-21 was isolated in 38% yield and with 99% optical purity, whereas the unwanted (i )-stereoisomer 22 was recycled in a three-step procedure. Changing the support to Celite 521 significantly increased the reaction rate, as did rais-... 

Dioxopyridoquinoline-2,8-dicarboxylic acids, cinnoline-3-propionic acids and 4-oxoquinoline-3-tetrazoles The pyridoquinoline dicarboxylic acid series has been explored by Upjohn and ICI (53- J). An angular pyridoquinoline, ICI 74,917 (bufrolin), is active in man by the aerosol route (fifi). The linear compound A (LXXXIX) is reported by Upjohn workers to be orally active in the PCA procedure (59). 

Aryloxamic acids, and aroylaminobenzoic acids Upjohn s aryloxamic acid, lodoxamide (U 42,585 E), (XCIV), is 2500 times more potent intravenously than DSCC f661. being the most potent agent thus far reported. However, this compound is 100-1000 fold less potent orally than intravenously, with inhibition in the PCA procedure obtained with oral doses between 0.1 and 10 mg/kg (g ) Activity has been reported in man following aerosol administration (fi7)- Further details on this series are discussed in the next chapter. 

Nurses were instructed to separate, as completely as possible, the polypropylene-based Excel bag from the NR stopper and from other types of infusion containers, mainly made from PVC. Administration sets, mainly consisting of PVC, were also removed from the bag prior to disposal in the waste container. The waste containers were collected by a forwarding agency and brought to Pharmacia Upjohn where they were checked for mistakes in the sorting procedures. Samples were then taken for material characterisation and for manufacturing trials. Two possible secondary applications were identified boxes for waste collection and flower pots. 

Germany), followed by injection of 200-450 mg microspheres (Spherex, Pharmacia and Upjohn, Erlangen, Germany) for vascular occlusion was applied slowly under fluoroscopic control until stasis of blood flow was observed. Generally, the patients tolerated the TACE procedure well and all patients were discharged on the same day after TACE treatment. No fatal or major complications related to the TACE treatment were observed. 

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