International Journal of Science and Research (IJSR) ISSN (Online): 2319-7064 Index Copernicus Value (2015): 78.96 | Impact Factor (2015): 6.391 Improved Process for the Preparation of Cetilistat from Isatoic Anhydride

Sridhar Prasangi1&2, Satynarayna2, YLN Murthy1&2

1Dravidian University, Srinivasa vanam, Kuppam-517426, Chittor, Andhra Pradesh 2Department of organic chemistry, Andhra University, Waltair, Visakhapatnam-530003 Andhra Pradesh

Abstract: 2-Amino,5-methyl benzoic acid on reaction with triposgene or phosgene gas in polar solvent or nonpolar solvent to produce isatoic anhydride. Isotonic anhydride on treating with Cetyl chloroformate to produce Cetilistat with good purity and yield.

Keywords: Cetilistat, triglycerides and synthetic lipase inhibitor

1. Introduction Takeda, under license from Norgina, is developing Cetilistat Cetilistat is a drug designed to treat . It acts in the (ATL-962), an oral non-absorbed synthetic lipase inhibitor same way as the older drug (Xenical) by inhibiting for the potential treatment of obesity in patients with or pancreatic lipase, an that breaks down triglycerides without diabetes in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable 2. Detailed Description free fatty acids and are excreted undigested. In human trials, Cetilistat was shown to produce similar weight loss to As shown in literature 1 Cetilistat can be prepared by Orlistat, but also produced similar side effects such as oily, reacting 2-amino-5-methyl benzoic acid with cetyl loose stools, , frequent bowel movements, chloroformate (Hexadecyl chloroformate) in a 2suitable and flatulence. It is likely that the same precautions would solvent like DMF, DMAC, pyridine etc. To get carbamate apply in that absorption of fat-soluble and other intermediate. Which on cyclizing in presence of cyclizing fat-soluble nutrients may be inhibited, requiring agent like methyl chloroformate, CDI or BOC to get supplements to be used to avoid deficiencies. Cetilistat with good yield and purity. O

O OH

Cl O Pyridine O OH N H O O NH2

C8H9NO2 Mol. Wt.: 151.16 C17H33ClO2 C25H41NO4 Mol. Wt.: 304.9 Mol. Wt.: 419.6

Methyl chloroformate

O

O

N O

C25H39NO3 Mol. Wt.: 401.58

column purification

O

O

N O

C25H39NO3 Mol. Wt.: 401.58

Volume 6 Issue 4, April 2017 www.ijsr.net Licensed Under Creative Commons Attribution CC BY Paper ID: ART20172611 1379 International Journal of Science and Research (IJSR) ISSN (Online): 2319-7064 Index Copernicus Value (2015): 78.96 | Impact Factor (2015): 6.391 We prepared the same material by 4 using isatoic anhydride and cetyl chloroformate in a suitable solvent with high yield and purity which shown in figure -1.

3. Experimental resulting Methelenedichloride solvent is evaporated under reduced pressure, the resulting residue is diluted in dimethyl All the Chemical and reagents used were purchased from acetamide (500 ml) and added cetyl chloroformate(0.73 Aldrich. All the solvents were of analytical grade. Thin- moles) the resulting reaction mass is stirred for 2-3 hours, layer chromatography (TLC) was checked by Merck AL after reaction completion, is added to reaction mass, silica gel 60 F254 plates and visualized under UV light. IR filtered, washed with water. The wet crude material is spectra were recorded in KBr pellet with a shimazu purified in ethyl acetate to give cetilistat as white solid (185 spectrum gx FTIR instrument and all the diagnostic, intense g 70% yield) peaks are reported. 1H NMR and 13C NMR spectra were recorded in DMSO- d 6 with a Varian Mercury plus 400 Example: 2 MHz and 100 MHz instruments respectively. All the Aminomethylbenzoic acid (100 g, 0.661 moles) is treated chemical shifts were reported in δ (ppm) using TMS as an with triphosgene (30 g) in THF (300 ml) at 0-5°C, the internal standard. The 1H NMR chemical shifts and coupling reaction mass is heated to reflux and maintained for 3-4 constants were determined assuming first-order behavior. hours under reflux. After reaction completion, the mass is Multiplicity is indicated by one or more of the following: s washed with sodium bicarbonate solution and water, the (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br resulting THF solvent is evaporated under reduced pressure, (broad), ABq (AB quartert); the list of coupling constants the resulting residue is diluted in dimethyl acetamide (500 (J) corresponds to the order of multiplicity assignment. ml) and added cetyl chloroformate(0.73 moles) the resulting Mass spectra were recorded on a Shimadzu LCMS-QP 1000 reaction mass is stirred for 2-3 hours, after reaction mass spectrometer. Melting points were determined in open completion, water is added to reaction mass, filtered, washed glass capillaries on a Stuart SMP30 apparatus and are with water. The wet crude material is purified in isopropyl uncorrected. All the reactions were performed under inert ether to give cetilistat as white solid (185 g 70% yield) atmosphere. Example: 3 4. Preparation of Cetilistat Isatoic Anhydride Aminomethylbenzoic acid (100 g, 0.661 moles) is treated with triphosgene (30 g) in ethyl acetate (400 ml) at 0-5°C, Example: 1 the reaction mass is heated to reflux and maintained for 3-4 Aminomethylbenzoic acid (100 g, 0.661 moles) is treated hours under reflux. After reaction completion, the mass is with triphosgene (30 g) in dichloromethane (500 ml) at 0- washed with sodium bicarbonate solution and water, the 5°C, the reaction mass is heated to reflux and maintained for resulting ethyl acetate solvent is evaporated under reduced 3-4 hours under reflux. After reaction completion, the mass pressure, the resulting residue is diluted in dimethyl is washed with sodium bicarbonate solution and water, the acetamide (500 ml) and added cetyl chloroformate(0.73 moles) the resulting reaction mass is stirred for 2-3 hours, Volume 6 Issue 4, April 2017 www.ijsr.net Licensed Under Creative Commons Attribution CC BY Paper ID: ART20172611 1380 International Journal of Science and Research (IJSR) ISSN (Online): 2319-7064 Index Copernicus Value (2015): 78.96 | Impact Factor (2015): 6.391 after reaction completion, water is added to reaction mass, filtered, washed with water. The wet crude material is purified in isopropyl alcohol to give cetilistat as white solid (185 g 70% yield)

References

[1] Bettina Holzer , Herbert Diehl, US7396952 B2, July 2008 [2] Zhang Yu , Wang Huajuan , CN105884706 A, Aug, 2016 [3] Chen Jie , Liang Jie , Du Changyong , Chen Junwei , Ye Jian , Chen Xiaoyong., CN103936687 A, Jul , 2014

Volume 6 Issue 4, April 2017 www.ijsr.net Licensed Under Creative Commons Attribution CC BY Paper ID: ART20172611 1381