Isoxazoline Synthesis

The piperidine nitrogen in haloperidol is oxidised, by oxidative dealkylation, to piperidine metabolites and fluorophenylcarbonic acids. The butyrophenones carbonyl in haloperidol is reduced to carbinol which then forms hydroxyhaloperidol, a metabolite of haloperidol with reduced activity. Intrinsic clearance of haloperidol is due to glucoronidation by uridine diphosphoglucose glucuronosyltransferase, oxidation by cytochrome P450 and reduction by carbonyl reductase. The elimination half-life for haloperidol is 12-38 hours. Complete elimination of an oral dose of haloperidol takes 4 weeks.

CH3 175 83.06% 287-289ºC 4. -OCH3 191 86.03% 275-277ºC 5. 204 78.78% 295ºC Step-3 Synthesis of 2-Methyl benzoxazin -4(3H)-one53 (4) Anthranilic acid (0.1M, 18g) was taken in acetic anhydride and refluxed under anhydrous conditions for 4 hrs. Excess of acetic anhydride was then distilled off under reduced pressure. Obtained product was immediately used for next step.

d. Nirav Kapadia and others uses Oxa-pictet-spengler reaction as one of the key steps in the synthesis of new isochroman heterocycles containing a 4, 5, 6a,7-tetrahydrodibenzo[de,g]chromene and further performed the acidic cleavage of molecule to form phenanthrene alkaloids(33). e. Santosh J. Gharpure et al worked on stereoselective synthesis of oxazino[4,3-a]indoles via oxa-Pictet–Spengler reaction of indoles having N-tethered vinylogous carbonate(26). Furthur optimization of reaction conditions were done and explained in table 19& 20. Table 19. Scope of the Oxa-Pictet-Spengler reaction for the synthesis of oxazinoindoles ENTRY R1 R2 R3 PRODUCT YIELD DIASTERIOMER RATIO 1 H H Ph 69l 85 >19:1 2 H H CH2OBn 69a 60 >19:1 3 H ----------(CH2)4-----------

N O O H2SO4 rt, 5 min. + N N N O O O Cl Cl Cl N O O H H Cl 32 34 35 32 33 10 Mono-halogenation (-Cl, -I, -Br) of isatin (32) can be achieved by reacting Nhalosaccharins 36 with isatin in the presence of SiO2 at r.t to specifically produce the 5-halo derivatives 37 as reported by de Silva and de Mattos.20 This method is an alternative to the use of highly toxic and corrosive Cl2 and Br2, which can lead to other products such as 5,7-dibromo- 3,3-dialkoxyoxindole when the bromination of isatin is attempted in alcoholic media.22 N O O SiO2 CH2Cl2 , rt. + N O O H H X S N O O O X X = Cl, Br, I N-Alkylation of Isatin Various methods have been used for the preparation of N-alkylated isatins which can be successfully achieved under basic conditions using alkyl chlorides, bromides, and iodides; as well as reactive allyl-, benzyl-, and propargyl halides. Conventional heating is often employed to produce the N-alkylated isatins from temperatures of from 40-100ºC under reflux. In general, the N-alkylation of isatin proceeds by reacting the isatin (32) substrate with any variety of base and solvent combination shown in Table 1, to

5. Results and Discussions 5.1 Methyl erucate synthesis 5.1.1 Chemical analysis of erucic acid Physicochemical properties of erucic acid used for the synthesis of sucrose erucate were analyzed. The results of analysis are depicted in Table 5.1 Table 5.1 Analysis of erucic acid Acid value 166.03 ± 0.9 mg KOH/gm Iodine value 78.04 ± 1.2 g I2/100gm Saponification value 168.05 ± 0.8 mg KOH/gm 5.1.2 Analysis of methyl erucate After synthesis and purification of synthesized methyl erucate general characteristics of product were tested. The results obtained are shown in Table 5.2 and Figure 5.1 Figure 5.1 Color of methyl erucate Table 5.2 General characteristics of methyl erucate Color Light yellow Odour Consistency The results of chemical analysis

The hydroxyl group (-OH) of NaOH attacks an electrophilic carbon of >N-C=O which as rearrangement gives carbonial . This carbonial abstract proton from water to give NAG. The established over degradation of NAG to 4-MBA was also obseved in alkali condition. Degradation pathway of AN is shown in Fig.3. The isolated degradation products are subjected to Mass studies to obtain their accurate mass fragment patterns.

One noticeable exception is the so-called “Atwal modification” of the Biginelli reaction. In this scheme, an enone(a) is first condensed with a suitable protected urea or thiourea derivative(b) under almost neutral conditions. Deprotection of the resulting 1,4-dihydropyrimidine(c) with HCl or TFA leads to the desired DHPMs.20 Scheme-3: Shutalev et al described another approach to DHPMs synthesis. This synthesis is based on the condensation of readily available R-tosylated (thio)ureas(a) with the enolates of acetoacetates or 1,3-dicarbonyl compounds. The resulting hexahydropyrimidines(b) need not to be isolated and can be converted directly into DHPMs.

10.Mizui T, Sato H, Hirose F, Doteuchi M. Effect of antiperoxidative drugs on gastric damage induced by ethanol in rats. Life Sciences, 41, 1987, 755 – 763. 11.Rainsford KD, Whitehouse MW. Biochemical gastroprotection from acute ulceration induced by aspirin and relateddrugs. Biochemical Pharmacology, 29, 1980,1281 – 1289.

Bromination is a type of electrophilic aromatic substitution reaction where one hydrogen atom of benzene or benzene derivative is replaced by bromine due to an electrophilic attack on the benzene ring. The purpose of this experiment is to undergo bromination reaction of acetanilide and aniline to form 4-bromoacetanilide and 2,4,6-tribromoaniline respectively. Since -NHCOCH3 of acetanilide and -NH2 of aniline are electron donating groups, they are ortho/para directors due to resonance stabilized structure. Even though the electron donating groups activate the benzene ring, their reactivities are different and result in the formation of different products during bromination. In acetanilide, the lone pair of the nitrogen is delocalized into the

DOX differes from daunorubicin only by a single OH group (Arcamone et al., 1972). DOX is a broad spectrum anti-cancer drug having excellent efficacy in malignant lymphoma, pulmonary cancer, digestive and mammary cancer, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma and Hodgkin's disease (Johdo et al., 2003). DOX inhibits both the isoforms of topoisomerase II (Topo II)