The synthesis of 3-(Trifluoromethyl)cinnamic acid

3-(Trifluoromethyl)cinnamic acid is a critical intermediate of cinnalcet hydrochloride which is a calcimimetic agent developed by the American NPS Pharmaceuticals.  Three primary synthetic routes of 3-(Trifluoromethyl)cinnamic acid have been reported in the literatures.

The synthesis methods of 3-(Trifluoromethyl)cinnamic acid

1. Synthetic method 1

3-Trifluoromethylbenzaldehyde (50.0 g, 0.287 moles), malonic acid (32.90 g, 0.315 moles) and piperidine (3.66 g, 0.043 moles) in dry pyridine (80 ml) was heated at 110°C~115°C for 4-5 h.The progress of the reaction was monitored by TLC. On completion of the reaction, the mixture was cooled to room temperature and chilled water (400 ml, 0-5°C) was added to the reaction mass and stirred for 1 hour. pH of the reaction mass was adjusted to 2-3 with 2 N HCl solution (200 ml) at 5-10°C and stirred for 1 hour. The resulting solid was filtered, washed with chilled water (400 ml, 0-5°C) and dried at 50~55 °C to get 3-(Trifluoromethyl)cinnamic acid . (45 g, 72.52 %).^[1]

2. Synthetic method 2

(1)step 1:To a stirred mixture of 3-trifluoromethylaniline (250.0g, 1.55moles) and demineralized water (440ml) was added hydrobromic acid (754ml) over 1 hour at 0-5°C followed by addition of acrylonitrile (368ml) maintaining temperature 0-5°C. A solution of sodium nitrite (111g sodium nitrite in 160ml of water) was added at same temperature and stirring was continued for 1.5 hours followed by the addition of copper (I) oxide (14.6g). The reaction mixture was initially stirred at 0-5°C for 2 hours and then at 20~25°C for 1'5 hours. The product was extracted with toluene (200 ml x 3). The organic extracts were combined and washed with water (500ml x2). Toluene was removed under reduced pressure to give 395g of m-trifluoromethyl-α-bromohydrocinnamonitrile.

(2)step 2: A mixture of m-trifluoromethyl-α-bromohydrocinnamonitrile(385g) and hydrochloric acid (2.3L) was refluxed for 7.5 hours, cooled to 25~30°C followed by extraction with toluene (500ml x3). The combined organic extracts were washed with water and concentrated under reduced pressure to afford 374g of the crude title compound. The crude product was taken in toluene (600ml) and aqueous sodium hydroxide (1.0L, 15%) was added at 10~15°C and stirred for 15 minutes. The layers were separated and aqueous layer was washed with toluene (200ml x2), acidified with hydrochloric acid (500ml) at 10-15°C and extracted with toluene (500ml x3). The combined organic extracts were washed with water and concentrated under reduced pressure to afford tm-trifluoromethyl-α-bromohydrocinnamonic acid. Isopropanol (1.42 L) and benzyltriethylammonium chloride (10.85g)was added,and aqueous sodium hydroxide (340 ml, 56%) was added slowly. The temperature was raised to 55~60°C, stirred for 7 hours and isopropanol was removed in vacuo. Water (500ml) was added to the reaction mass, stirred and cooled to 0°C and acidified with hydrochloric acid (450ml). The solid was filtered, washed with water and dried in vacuo at 50°C to afford 204g of 3-(Trifluoromethyl)cinnamic acid.^[2]

Fig.1 The synthesis of 3-(Trifluoromethyl)cinnamic acid

3. Synthetic method 3

3-Trifluoromethylbenzaldehyde(10 g) was taken into a round bottom flask containing acetic anhydride(3.8 g) and stirred for 15 minutes. The reaction mass was heated to about 175℃ and stirred for about 5 hours. After completion of the reaction, the reaction mass was cooled to about 80℃ followed by addition of water(40 ml) and again stirring for 15 minutes. pH of the reaction solution was adjusted to about 10 by addition of 100 ml of 10%sodium carbonate solution and stirring for about 15 minutes. The water was distilled at about 110℃ under vacuum and the separated solid was filtered.The obtained filtrate was charged into a fresh round bottom flask and cooled to about 0℃. pH of the solution was adjusted to about 2 by the addition of concentrated HCl(25 ml) and stirred for solid separation. The separated solid was filtered and washed with water(40 ml). The resultant solid was dried under vaccum at about 50℃ to afford 2.4 g of 3-(Trifluoromethyl)cinnamic acid.^[3]

References

[1] Macleods Pharmaceuticals Limited, Process for preparing cinacalcet hydrochloride, [P]IN2007MU00555.

[2]Chidambaram, Process for preparation of cinacalcet hydrochloride,[P]WO2008035381.

[3]Dr. Reddy's Laboratories, Process for preparation of Cinacalcet hydrochloride,[P]WO2008058236.