Warfarin 17 yields

The preparation of warfarin derivatives via the catalysed Michael-type reaction of 4-hydroxycoumarins with 4-arylbut-3-en-2-ones is achieved with a ca. 20-fold increase in reaction rate and a twofold increase in yields, compared with traditional methods [60]. Similarly, tetra-H-butylammonium fluoride catalyses the reaction of nitrotoluenes with a,p-unsaturated esters under mild soliddiquid two-phase conditions [14] with increased yields, compared with those observed in the absence of the catalyst. 

Fig. 3.12 The ALIS affinity competition experiment 50% inhibitory concentration (ACE50) method. (A) The warfarin versus warfarin-De ALIS competition data from Fig. 3.9, normalized and plotted on a logarithmic axis, yields the ACE50 value, which is the titrant concentration at which the ligand binding is reduced by 50%. (B) Simulated...

Extension to cyclic Michael donors also met with marked success using imida-zolidine catalyst 54 (10 mol%) (Scheme 22) [95]. Conveniently, the reactions proceeded at room temperature using dichloromethane as the solvent and 1.05 equivalents of the Michael donor, representing a substantial improvement in the atom efficiency of the process. The synthetic utility of this transformation was exemplified by the one-step preparation of the anticoagulant (5)-warfarin (R = Ph, = Me, R = H 90% yield 80% ee) which could be recrystallised to optical purity (>99.9% ee) from acetone/water. 

Scheme 33 Hydroalkylation of 4-hydroxycomarin yields highly desirable warfarin derivatives...

The transformation could also be performed using a chiral enantiopure enol ether as dienophile. The best results were achieved with the isopropenyl ether 182b derived from cheap and commercially available (—)-(lR,2S,5R)-menthol. The cycloadduct was obtained with an endo/exo-selectivity of 4.1 1 and an induced dia-stereoselectivity of 88 12. Treatment of 178b with trifluoroacetic acid/water 19 1 provided (S)-warfarin 175 in an overall yield of 61% referred to 4-hydroxy coumarin 55 and an enantiomeric excess of 76% (HPLC), which could be increased to 95% ee by recrystallization using the purified endo-product 178b as substrate for the hydrolysis. In the same manner (S)-coumachlor 176 and (S)-acenocoumarol 177 were obtained with 56% overall yield and 93% ee and 59% overall yield and 95% ee, respectively. 

The influence of high intensity ultrasound on various reactions of 4-hydroxycoumarin in aqueous conditions has been studied <03S1286>. 4-Hydroxycoumarins and -thiocoumarins undergo an asymmetric Michael addition to a, 3-unsaturated enones in the presence of imidazoline catalysts. High yields and enantioselectivities are observed and the method has been used to prepare kg quantities of enantiopure warfarin (Scheme 24) <03AG(E)4955>. 

Another example of the synthesis of a compound with pharmaceutical relevance is the chemical transformation of rac-warfarin into enantiomerically pure (R)- or (5)-warfarin. In the first step, rac-warfarin is oxidized to the corresponding ot,p-unsaturated ketone. The latter can be easily hydrogenated to the desired enantiomer by application of the appropriate DuPHOS-catalyst (eq 11). Prior transformation of dehydrowarfarin into the sodium salt or its methyl ether improved the yield and suppressed side reactions. Simultaneously, the enantioselectivity of the hydrogenation product was enhanced. The (5,5)-ethyl-DuPHOS-complex leads to R-configured warfarin. 

When chiral ketones are reduced, they yield two possible diastereomeric or epimcric alcohols. For example, the IRK +) enantiomer of the oral anticoagulant warfarin undergoes extensive reduction of its side chain keto group to generate the (R.S)( +) alcohol as the major plasma metabolite in humans. - Small amounts of the ( ./ )(+) diastereo-nier also ate formed. In contrast, the (5)(-) enantiomer undergoes little ketone reduction and is primarily 7-hydroxy-bied (ie.. aromatic hydroxylatton) in humans. 

In 1996, Murphy et al. published the results of their national survey of hospital-based pharmacokinetics services. Altogether, 252 questionnaires were mailed to all respondents of the 1994 American Society of Health-System Pharmacists (ASHP) national survey of hospital-based pharmaceutical services " who indicated that their institution provided pharmacokinetics services. The response rate was 42.1% (n=106) however, only 98 surveys had complete data thus yielding a net response rate of 40.2%. Aminoglycosides were the main focus (60.8 27.7% of total) of pharmacokinetic consultations, followed by vancomycin (21.1 18.3%), theophylline (4.6 7.4%), other (3.6 16.0%), warfarin (3.1 11.1%), digoxin (2.2 6.1% ), phenytoin (l.2 3.0%), lithium... 

Chiral to diastereoisomer transformations a second chiral center is introdueed into the drug either by reaetion at a prochiral center or via conjugation with a chiral conjugating agent. Examples include the side-chain aliphatic oxidation of pentobarbitone and the keto-reduction of warfarin to yield the eorresponding diastereoisomeric alcohol derivatives or the stereoseleetive glueuronidation of oxazepam [113]. 

Whole body level parameters are determined by multiple organ parameters, which in turn are a reflection of multiple macromolecular parameters. Thus, in the case of a pair of enantiomers, the observed stereoselectivity for a particular parameter is dependent on the level of organization that the parameter represents and may be either amplified or attenuated [94]. For example, in the case of warfarin, the enantiomeric ratio (R/S 1.93) in half-life is determined primarily by differences in volume of distribution (R/S 1.83) rather than the modest difference in elearanee (R/S 1.05). In contrast, examination of the alternative metabolic routes generates marked differences in stereoselectivity, e.g., aromatic oxidation at the 6-, 7-, and 8-positions of the coumarin ring yields enantiomeric ratios of R/S 1.19, S/R 6.33, and R/S 5.2, respectively. These, together with the... 

The biotransformation of a racemic mixture of the R. and S-isomers of warfarin was studied in man after oral administration. Urinary metabolites were the result of two types of reactions. One of them involved hydrojgrlation at either the 6- or 7-position of the coumarin portion, while the other involved a reduction of the acetonyl side chain to yield two diastereoisomeric alcohols. 

A highly enantioselective organocatalytic Michael addition of 4-hydroxycouma-rines and related compounds to a,p-unsaturated ketones has been also achieved using imidazolidine catalyst 137 [213]. The reaction, which gives high yields and enantioselectivities for a wide range of cyclic 1,3-dicarbonyl compounds and enones, has been successfully employed for the asymmetric synthesis of the anticoagulant warfarin (Scheme 2.78) and derivatives [213], With respect to the reaction mechanism, very recent studies have demonstrated that the truly active catalyst in the process was the chiral diamine 138, which is formed in catalytic amounts under the reaction conditions by reaction with the hydroxycoumarine (Schane 2.79)... 

The intermediate of the reaction is then postulated to be a chiral diimine formed from the diamine and the enone. In this intermediate one of the faces of the electrophile is efficiently shielded from the nucleophilic attack. This finding led to the authors to explore the use of chiral Cj-symmetric diamines as organocatalysts in the conjugate addition giving higher yields (up to 98%) and enantioselectivities (up to 92% ee) for the synthesis of warfarin (Scheme 2.79) [216]. 

Mei and coworkers utilised primary amine thiourea 44 based on the (IS,25 )-diphenylethylene-l,2-diamine backbone for the enantioselective Michael reaction between 4-hydro>ycoumarin and a,p-unsaturated ketones (Scheme 19.49). The products were isolated in high to excellent yields (up to 97%) and in good to high enantiomeric excesses (up to 95% enantiomeric excess). This method gives access to enantiopure (S)-warfarin, which is an anticoagulant agent. 

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