2",6-Dihydroxy derivative

The parent A1-THC-7-oic acid (lower left of Figure 4) has since been found in the monkey by Wall and Brine (14) and in the mouse, Harvey and Paton (15). The latter authors have also reported the 3"-hydroxy derivative and the 2",6-dihydroxy derivative as metabolites in the mouse (16). A series of acids in which the carboxyl group is in the side-chain have been isolated by Martin ot ad. (17). The structures were established by mass spectral analysis and by conversion to the... 

The free mercapto compounds (72) are extremely stable towards alkalis and acids, but they are quickly attacked by oxidizing agents.15,126 Disulfides (73) or disulfonic acids (74) are obtained, depending upon the conditions. On melting with alkali the latter compounds do not yield 2,6-dihydroxy derivatives but cleavage products. 

The discovery that vitamin was metabolized to biologically active derivatives led to a significant effort to prepare 25-hydroxy vitamin and, subsequendy, the 1 a-hydroxy and 1,25 dihydroxy derivatives. Initial attempts centered around modification of steroidal precursors, which were then converted to the D derivatives by conventional means. 

Only the potentially 2,4-dihydroxy derivatives of furan and thiophene are known and these exist in the solid state and in polar solvents as the monoenols (82) (71T3839). However, in non-polar solvents the furan derivatives exist predominantly in the dioxo form (83). The 2,5-dioxo structure (84) is well established for X=0, NR, S and Se (71BSF3547) and there is no evidence for intervention of any enolic species. The formal tautomer (85) of succinimide has been prepared and is reasonably stable (62CI(L)1576). 

The three dihydroxy derivatives of benzene may be naned as 1,2-, 1,3-, and 1,4-benzenediol, respectively, but each is more faniliaily known by the common nane indicated in parentheses below the structures shown here. These common names are permissible lUPAC nfflnes. 

This synthesis is thus suitable preparing 6,7-dihydroxy derivatives (substituted 8-azaxanthines). However, with regard to the 1- or... 

Demethylation of trequinsin (3) with a 65 35 mixture of AcOH and 48% HBr at 115 °C for 3 h gave mainly 10-hydroxyl derivatives 148 (R = r = H), which was accompanied by traces of its 9-hydroxyl and 9,10-dihydroxy derivatives. In boiling 48% HBr for 2 h its 9,10-dihydroxy derivative formed in 63% yield (98IJC(B)1). 9-Methoxy group of 3 and that of its 2-[(2,6-dimethyl-4-carboxyphenyl)imino] derivative 178 (R = COOH) was selectively demethylated by the treatment with 60% NaOH and EtSH in HMPA. Treatment of 3 with pyridine HCl in boiling pyridine for 20 min afforded its 9,10-dihydroxy-3-desmethyl derivative in 65% yield. 4 -Hydroxymethyl... 

Various nucleophiles undergo addition to oxepins to give functionalized cyclohexadienols. Thus, terf-butyl oxepin-4-carboxylate when treated with a methanolic solution of lithium hydroxide gives /ert-butyl ow .v-5-hydroxy-6-methoxycyclohexa-l,3-diene-1-carboxylate (3a) in 56% yield.156 When dioxane is used as solvent, the respective dihydroxy derivative 3b is obtained in 30 % yield. Sodium azide reacts with oxepin to give mws-6-azidocyclohexa-2,4-dien-l-ol (3c) in 55% yield.212... 

The recent synthesis of (—)-tetracycline by Myers and co-workers incorporates a biocatalytic step in the first stage which oxidizes benzoic acid aerobically to an a,f)-dihydroxy derivative in the presence of a whole-cell mutant strain of Alcaligenes eutrophus. Figure 4.61 shows a reduced tree diagram for the synthesis and Table 4.28 summarizes the metrics parameters. 

As can be seen, in both the 5,6- and the 7,8-dihydroxy-2(lH)quinolinone pathways, after initial hydroxylation adjacent to the N-heteroatom, the benzene moiety of the quinoline ring is transformed to a dihydroxy derivative 5,6- or 7,8-, respectively, which subsequently undergoes ring cleavage. However, neither of them involves C—N bond cleavage and consequently do not lead to denitrogenated products. 

The biosynthesis of pregnenelone (112) in mammals has been well documented [1] it is known to be produced from cholesterol (1) via its 20,22-dihydroxy derivative (121) (Scheme 19A). The origin of 112 has been investigated in the sponge Amphimedon compressa. At the present time it is not known whether cholesterol and its 20,22-dihydroxy derivative serve as precursors for this pregnane in A. compressa however a new pathway (Scheme 19B) has been found to operate [89]. This involves the conversion of 22-dehydro sterols (e.g. stigmasterol, 122) to pregnenelone. The mechanism is believed to... 

Figure 4.28 Hydrolysis of epoxy groups forms 1,2-dihydroxy derivatives that can be oxidized with periodate to create reactive aldehydes.

Dihydroxy derivative 277 when treated with sulfur monochloride provided in 65% yield sulfur-bridged diketopiperazine structure 298 (Scheme 73) (77JOC948). 

Cholanic acid C24H40O2, a monobasic saturated acid containing four hydroaromatic rings, is the parent substance of the two natural acids, which are its trihydroxy- and dihydroxy-derivatives. It is very highly probable that the following structural formula for cholic acid is correct ... 

That the metabolism of melphalan occurs by the same reaction mechanism as that of mechlorethamine has been demonstrated in in vitro studies [65]. Under physiological conditions of temperature and pH, formation of the first and second aziridinium intermediates en route to the bis(hydroxyethyl) metabolite occurred with rate constants of ca. 0.017 and 0.041 min-1, respectively. After 60 min, ca. 2/3 of the drug had been converted to the monohydroxy and dihydroxy products in comparable amounts. In the presence of a phosphate buffer, competition between hydrolysis and phosphatolysis was seen, such that at completion of the reaction (4 h) the two major products were the dihydroxy and the hydroxy/phosphate metabolites, with the dihydroxy derivative produced in small amounts. Similar hydrolytic dehalogena-tion has also been observed for ifosfamide in acidic aqueous solution [69]. 

Reduction of the carboxylic group of an AA and subsequent treatment with ethylene oxide afforded a dihydroxy derivative that cyclized in 70% sulfuric acid. From l-AAs morpholines with the (R)-configuration at the chiral center were obtained (Scheme 41) (80T409). Esters of AAs, after... 

Well-established routes to dibenzothiophenes such as reaction of 2,2 -dihydroxy derivatives of biphenyl with phosphorus pentasulfide are still encountered in the literature but have been omitted from the present work as they have already been well documented. ... 

Acetonides 38 were prepared by the reaction of 37 and A-methylmorpho-line oxide (NMO) in the presence of a catalytic amount of OSO4, followed by treatment with 2,2-dimethoxypropane in the presence of Dowex (H ) resin (93JOC6083). In aqueous acetonitrile, the (35,4/ )-3,4-dihydroxy derivative 39 was the product (94JOC1358). 

Very recently, chiral crown ethers incorporating 9,9 -biphenanthryl (158) and 4,4 -biphenanthryl (159) moieties have been prepared from the corresponding optically active 10,10 -dihydroxy and 3,3 -dihydroxy derivatives, respectively. Both 20-crown-6 macrocycies, for example, (S)-130, containing one chiral unit and 22-crown-6 macrocycies, for example, (/U )-131, containing two chiral units are known. 

Reacting this with sodium methoxide leads to the formation of an epoxide— 9-(2, 3 -anhydro- 8-luxofuranosyl)adenine (36.1.9). Finally, heating this epoxide with sodium acetate or benzoate opens the epoxide ring in the dimethylformamide-water system to make the corresponding dihydroxy derivative, vidarabine [12,13]. 

The )>-form(IV) has so far remained elusive. The rate of tautomerisation is proposed as playing a key role in determining the hydrolysis pathway. Thus, if the rate of tautomerisation is slower than the subsequent hydrolysis, nucleophilic attack at the same phosphorus leads to a geminal dihydroxy derivative. This undergoes tautomerisation to give a hydroxy oxophosphazadiene. Alternatively faster tautomerisation leads to nongeminal attack (Scheme 11) [154]. 

Cunninghamella blakesleana affords the 7/3-hydroxy-, 16a-hydroxy-, 16,17-dihydroxy-, and 7/3,16a-dihydroxy-derivatives. The angelic acid ester of ent-15/3-hydroxykaur-16-en-19-oic acid (73) and its 16,17-epoxide (perymenic acid) have been obtained from Perymenium ecuadoricum (Compositae). A group of... 

An alternative synthesis of 22,23-dihydroergosteryl acetate involved hydrogenation of the epidioxide (249) to the saturated 5a,7a-dihydroxy-derivative (250). This was followed by an improved carefully controlled dehydration with... 

Microbial and enzymic transformations of steroids have been reviewed. 5a-Pregnane-7,20-dione gave a reasonable yield of the la, 12/3-dihydroxy-derivative on incubation with Calonectria decora High yields of 10 8-hydroxy-19-nortes-tosterone were obtained by incubation of 19-nortestosterone with Rhizopus arr-hizus (Fischer 11). Oxidation of canrenone with a Penicillium species provided the 15a-hydroxy-derivative (348) which is a product of human metabolism of spironolactone.16j8-Hydroxylation of androstenolone, androst-4-ene-3,17-... 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

The carbonyl group carbon shows the largest upfield shift due to the electrostatic field effect in the dioxolane and dihydroxy derivatives this is countered by the polarization of the free oxygen electron pairs. 

Next, 15-LOX oxidizes both 15-HPETE and 5-HPETE to LTA4 (Figure 26.4). Rat peritoneal monocytes and human leukocytes are also able to oxidize AA into the dihydroxy derivative, 5(S), 15(,V)-dihydroxy-6,l 3-/ran.v-8,11 -c/.v-cicosatctracnoic acid (5,15-DiHETE). It has been shown [18] that 5,15-DiHETE was formed by a double oxidation of AA catalyzed by both 5-LOX and 15-LOX lipoxygenases (Figure 26.5). It is interesting that the... 

Pharmacokinetic studies revealed rapid systemic absorption after intramuscular administration of dexamethasone, with peak plasma levels attained at 0.5 h and 6 h in dogs and rats, respectively. It is rapidly excreted in urine and feces. Its biotransformation profile is comparable in rats and humans and mainly involves hydroxylation to 6-hydroxy- and 2-dihydroxy-derivatives followed by conjuga-... 

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