Reaktion #79434

Reaktionsgleichung

acid ( 2 )

Ethyl 4-amino-3-chlorobenzoate

3-chloro-procainamide

Carbonyl diimidazole

CO2

N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide

→

desired product

4-Amino-3-chlorobenzoic acid

Lösungsmittel

THF

CH2Cl2

MeOH

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturincreased rapidly
2. 2
   Temperaturthe mixture was warmed to 45° C. for fifteen minutes
3. 3
   Sonstigehad reacted
4. 4
   Temperaturthe reaction mixture was warmed to 55° C
5. 5
   workup.WAITAfter 30 minutes

Vorschrift

3-chloro-procainamide, free base, [N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide, free base] (1b). The acid (2), 10 g (0.058 moles) was dissolved in 800 mL of anhydrous THF. Carbonyl diimidazole, 11.1 g (0.067 moles), was added in one portion and the mixture was warmed to 35° C. CO2 began to slowly evolve and then increased rapidly. After one hour, all evolution of gas ceased and the mixture was warmed to 45° C. for fifteen minutes to insure that all of the acid had reacted. N,N′-diethylenediamine, 7.5 g (0.65 moles) was added dropwise over five minutes and then the reaction mixture was warmed to 55° C. After 30 minutes, a TLC of the mixture (CH2Cl2:MeOH, 3:1) showed that the reaction was complete, producing the desired product (Rf 0.4) along with a minor nonpolar impurity (Rf 0.8) and polar impurities (Rf 0.1). The TCL did not change after stirring overnight at 55° C. The solvent was removed on a rotary evaporator at 50° C. and then 100 mL of water was added to destroy any unreacted carbonyl diimidazole, producing a biphasic mixture. The free base was extracted into CH2Cl2 (3×100 mL), and dried over anhydrous K2CO3, and evaporated to give 20 g (>100%) of a brown oil. Attempts to prepare a crystalline salt (sulfate, succinate, tosylate, and adipate) failed. Simple chromatography on 25 g of silica, eluting with hexane:EtOAc (2:1) gave 14.3 g (91%) of 1b as clear tan oil, homogeneous by TLC. The structure of the free base (1b) is shown in FIG. 5. 1H NMR (CDCL3) d 7.75 (d, J=0.8 Hz, 1H, ArH), 7.52-7.48 (dd, J=0.8 Hz, 1H, ArH), 6.84 (bs, 1H, NH), 6.77-6.74 (d, J=2.8 Hz, 1H, ArH), 3.49-3.43 (q, 2H, J=1.8 Hz, CH2NHCO), 2.66-2.54 (m, 6H, (CH2)3N, 1.07-1.02 (t, J=2.4 Hz, 6H, N(CH2CH3)2). IR (KBr) cm−1, 3475, 3320 (NH2, m), 1620, 1600 (C═O, s). MS (El) m/e 269 (M+), 271 (M+2), 240 (M=−Et), 197 (M+−NEt2), 154 (M+−NCH2CH2NEt2), 86 (base peak, M+−CH2NEt2) Anal. Calc'd for C13H20N3—OCl: C, 57.88; H, 7.47; N, 15.58. Fd. C, 58.05; H, 7.56; N, 15.30.

Quelle