9-[(4-Carboxy-2,6-diMethylphenoxy)carbonyl]-10-(3-sulfopropyl)acridiniuM Inner Salt synthesis

Yield:946423-58-1 62%

Reaction Conditions:

with hydrogenchloride;water at 110; for 4 h;Product distribution / selectivity;

Steps:

2; 3

Example 2; [0076] N-Alkyation on a gram scale of 2',6-dimethyl-4'-methoxycarbonylphenyl acridine-9-carboxylate with propane sultone in FBMIMIfPFl: Synthesis of 2',6'- dimethyl-4'-carboxyphenyl-10-sulfopropylacridinium-9-carboxylate.; [0077] To an 8 dram vial was added 2.0 g (5.19 mmol) of the acridine ester, 15 g(52.8 mmol) of l-butyl-3-methylimidazolium hexafluorophosphate (Fluka) and 6.34 g (51.9 mmol) of distilled 1,3-prυpane sultone under nitrogen. This sealed vial was heated to 155⁰C for 24 hours. Then the reaction mixture was cooled to 4O⁰C and added drop wise into 500 ml of ethyl acetate with stirring which gave a yellow precipitate. The mixture was stirred at room temperature for 2 hours and filtered. The filter cake was washed with ethyl acetate (50 ml x 3) and dried under high vacuum which gave 6.19 g of a yellow solid which was then treated as follows.[0078] The above 6.19 g of crude acridinium ester was added to 80 ml of HCl solution (8 ml concentrated HCl and 72 ml de-ionized water). The reaction mixture was heated to HO⁰C for 4 hours and then cooled to 2-8⁰C overnight. A yellow precipitate was formed which was filtered. The filter cake was washed with de-ionized water (40 ml x 3) and diethyl ether (20 ml x 2) and dried under high vacuum over P₂O₅ which gave 1.68 g yellow powder (66% yield from 2',6'-dimethyl-4'-methoxycarbonylphenyl acridine-9-carboxylate, 94% purity by HPLC).; Example 3; [0079] N-Alkyation on a gram scale of 26-dimethyl-4'-methoxycarbonylphenyl acridine-9-carboxylate with propane sultone in [BMIMl [BF41: Synthesis of 2',6'- dimethyl-4'-carboxyphenyl-10-sulfopropylacridinium-9-carboxylate.; [0080] To an 8 dram vial was added 1.0 g (2.6 mmol) of the acridine ester, 10 g(44.2 mmol) of l-butyl-3-methylimidazolium tetrafluoroborate [BMIM]BF₄] (Fluka) and 3.18 g (26.0 mmol) of distilled 1,3-propane sultone under nitrogen. This sealed vial was heated to 155⁰C for 24 hours. Then the reaction mixture was cooled to room temperature which gave a red, clear liquid (83% conversion to product by HPLC). The above red clear liquid of the acridinium methyl ester was added to a 30 ml of 1 M HCl solution. The reaction mixture was heated to HO⁰C for 4 hours and then cooled to room temperature which gave a red solution. The reaction mixture was poured into a 1000 ml of de-ionized water and a yellow precipitate was formed. The mixture was kept in the refrigerator overnight. The yellow precipitate was then filtered and washed with de- ionized water (40 ml x 3) and diethyl ether (40 ml x 3). It was then dried under high vacuum over P₂O₅ which gave 0.793 g of product as a yellow powder (62% yield from acridine ester, 81% purity by HPLC).

References:

WO2009/67417,2009,A1 Location in patent:Page/Page column 26-28