Synthesis of New Chiral and Nonchiral Pyrido [ 3 , 2e ] , [ 1 , 3 , 4 ] oxadiazine Derivatives

A chiral series of 6,7-dichloro-3-[3-(2,2-dihalovinyl)-2,2dimethylcyclopropyl] -1H-pyrido [3,2-e],[1,3,4] oxadiazines (a-f) and a nonchiral series of 3-substituted, 6,7-dichloro-1H-pyrido [3,2-e][1,3,4] oxadiazines (a-g) have been synthesized. The synthesized compounds were characterized by IR, H-NR, HPLC and mass spectral data.


Scheme 1 Experimental
Melting points were determined on a LABINDIA MR.VIS visual melting range apparatus and are uncorrected.Reactions monitored by using Shimadzu SPD 10AV HPLC.Solvent system (mobile phase) acetonitrile -methanol-water (60:30:10) and 240 nm.HPLC column used was C-18 and flow rate maintained was 1 mL/min.IR spectra in KBR (cm -1) were recorded on Jasco FT/IR-410 series spectrophotometer and 1 H NMR spectra were recorded (DMSO-d 6 ) on a Bruker 200MHz spectrometer using TMS as internal standard (chemical shifts are expressed in δppm.).GC-MS spectra were recorded on Polaris Q mass detector.
In a reaction set up of single necked flask, magnetic stirring and oil heating system, 5.0 g (0.01 mole) of above prepared hydrazonoate, 25 mL dimethyl acetamide (DMAC) solvent and 0.7 g of K 2 CO 3 as acid binder was taken.This was heated to 115-120 °C and maintained for 6 h.Distilled out DMAC under reduced pressure and to the left over residue added water and filtered.The filtered solid dried and crystallized with 20 mL methanol.Crystallized yield was 65.78%.Off-white crystalline solid; melting point was 180-182°C.
In a reaction set up of single necked flask, magnetic stirring and oil heating system, 5.0 g (0.012 mole) of above prepared hydrazonoate, 25 mL dimethyl acetamide (DMAC) solvent and 0.7 g of K 2 CO 3 as acid binder was taken.This was heated to 115-125 °C and maintained for 7 h.DMAC was distilled out under reduced pressure and to the left over residue, water was added and filtered.The filtered solid dried and crystallized with 25 mL methanol.Crystallized yield was 22.7 %.Off-white crystalline solid; melting point was 258-259 °C.
In a reaction set up of single necked flask, magnetic stirrer and oil heating system, 2.0 g (0.005 mole) of above prepared hydrazonoate, 25 mL DMAC solvent and 0.23 g of K 2 CO 3 was added as acid binder.This was heated to 140-145 °C and maintained for 4 h.
DMAC was distilled out under reduced pressure and to the left over residue water was added and filtered.The filtered solid dried and crystallized with 100 mL methanol, as solubility is very poor.The yield of buffer-white crystalline solid was 74%, melting point was 211-212 °C.
In a one necked 250 mL round bottom flask, 50 mL of dichloromethane solvent, TBAB catalyst was taken and then to this 10.8 g (0.05 mole) of ammonium salt of 3,5,6-trichloropyridine-2-ol was added.It was stirred using magnetic stirrer.It was thin white slurry.To this 7.8 g (0.55 moles) of benzoyl chloride was added slowly over 15 minutes.The addition of acid chloride was exothermic and hence temperature controlled between 30-42 °C.After addition of acid chloride, reaction mass was becomes thin with fine salt (ammonium chloride) precipitation.Further reaction was maintained between 40-42 °C for 4 h.To this mass 100 mL water was added and stirred.Separated layers and organic layer washed with 40 mL of 5% Na 2 CO 3 solution to remove any unreacted acid part.Organic layer further washed with water and dried over CaCl 2 .Product in dichloromethane solvent was concentrated to below 50 °C to remove solvent part and crude product re-slurried with 100 mL methanol and filtered.The yield of white crystalline solid was 93.9%.
In a set up of one necked 50 mL round bottom flask with magnetic stirrer, 25 mL methanol, 0.013 moles of 3,5,6-trichloropyridin-2-yl benzoate and 0.1 g PTSA was added.It was slurry.This mass was cooled to 18-20 °C by external cooling and to these 0.015 moles of hydrazine hydrate (80.0%solution) was added.Addition was exothermic and thin slurry converted into thick white slurry.This was maintained at 20-30 °C for 4 h.Reaction mass concentrated under reduced pressure at 45-50 °C.To this concentrated product 25 mL of pyridine was added and refluxed for 6 h.Then pyridine was distilled out under vacuum at 100-105 °C.To the residual part, water was added and filtered the product.The isolated crude product purified in 25 mL of methanol.The yield of buffer white solid was 62%, melting point was 175-177 o C. GC-MS: 283 (M + 1 peak).

Results and Discussion
The chiral acid mixture (3-(2, 2-dihalovinyl)-2,2-dimethyl cyclopropane carboxylic acid) used in the synthetic process was obtained from M/s Gharda Chemicals Ltd.The chiral mixture was resolved to get single isomer as well as recemic mixture for experimental purpose.The isolated acid was converted into acid chloride by reacting with thionyl chloride under controlled condition to preserve chiral purity.The input raw material i.e. 3,5,6trichloropyrine-2-ol was obtained from M/S Gharda Chemicals Ltd.This 3,5,6trichloropyrine-2-ol (198.5 g, 1.0 mole) was taken in 500 mL methanol solvent and dry ammonia gas at 30-35 °C was passed till ammonical pH.This was further refluxed for 1.0 h and then filtered at 30 °C to get ammonium salt.3,5,6-trichloropyridin-2-yl-3-(2,2dihalovinyl)-2,2-dimethylcyclopropanecarboxylate was prepared by reacting corresponding acid chloride with 3,5,6-trichloropyrine-2-ol ammonium salt in dichloromethane solvent in presence of DMAP catalyst at 40 °C.The quantity of ammonium salt taken was 10 mL excess than acid chloride and dichloromethane solvent was 100 mL per 0.05 mole scale.Similarly other carboxylates and sulfanyl acetates were prepared.Reacting 0.05 moles of these intermediate in 50 mL methanol and 0.055 moles of 80% hydrazine hydrate at 20 °C using PTSA catalyst, prepared the corresponding hydrazonoates.The novel derivatives of synthesized oxadiazine likely to show diverse biological activity.