Efficient and Practical Synthesis of Saflufenacil

Peroxidizing herbicides are substances that inhibit protoporphyrinogen oxidase (PPO), inhibiting the biosynthesis of chlorophyll due to the resulting active oxygen. Since PPO herbicides are fast-acting at low concentrations with effective herbicidal activity against many weeds, they have been evaluated as a class of herbicides that are safe for the environment, and they have become an important research subject. 1 – 3 Saflufenacil ( 1 , Scheme 1) is a uracil-based herbicide. This herbicide is a potent inhibitor of PPO and is labeled for the control of broadleaf weeds in corn, soybean, cotton and grain sorghum. 4 – 6

Peroxidizing herbicides are substances that inhibit protoporphyrinogen oxidase (PPO), inhibiting the biosynthesis of chlorophyll due to the resulting active oxygen. Since PPO herbicides are fast-acting at low concentrations with effective herbicidal activity against many weeds, they have been evaluated as a class of herbicides that are safe for the environment, and they have become an important research subject. [1][2][3] Saflufenacil (1, Scheme 1) is a uracil-based herbicide. This herbicide is a potent inhibitor of PPO and is labeled for the control of broadleaf weeds in corn, soybean, cotton and grain sorghum. [4][5][6] Two synthetic routes for the preparation of 1 have been reported, as shown in Scheme 1 and Scheme 2. The original synthetic route for 1 was developed by BASF as shown in Scheme 1. Using 2-chloro-4-fluorobenzoic acid (2) as the starting material, 5-amino-2-chloro-4-fluorobenzoic acid (4) was prepared from 2 through nitration and reduction successively in 48% yield over 2 steps. 7 2-(Dimethylamino)-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (5) was obtained through amidation and cyclization steps in 61% overall yield. 7 Treatment of compound 5 with compound 4 gave 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,5-dihydropyrimidin-1(2H)-yl)-4-fluorobenzoic acid (6) in 92% yield in refluxing AcOH. This was reacted with CH 3 I in K 2 CO 3 /DMF to give the benzoate compound 7, which was then treated with BBr 3 to obtain the benzoic acid intermediate 8 (80% yield over 2 steps). 8 Treatment of compound 8 with oxalyl chloride and N-methyl-N-isopropyl sulfamide (10) 7,9 successively gave the final product saflufenacil 1 in 16% yield over the last 2 steps. 10 This route has multiple synthetic steps, some of which have low yields, resulting in low overall yield and high production costs. In addition, some intermediates were separated and purified by column chromatography, a process which is not suitable for scale-up.
The synthetic route more recently reported by Liu's research group can be used to prepare saflufenacil, 11 as shown in Scheme 2. 2-Chloro-4-fluoro-5-nitrobenzoic acid (3) was prepared based on the reported method in 91% yield, 7 and this was heated with thionyl chloride to give the benzoyl chloride 11 in 97% yield. 7 N-Methyl-N-isopropyl sulfamide (10) was reacted with compound 11 to produce the N-(N-isopropyl-Nmethylsulfamoyl)nitrobenzamide compound 12 in 89% yield. 12 Compound 13 was obtained by catalytic hydrogenation of 12 in 90% yield. Compound 13 was treated with methyl chloroformate to form compound 14 in 92% yield. Compound 14 was reacted with ethyl 3-amino-4,4,4-trifluorobut-2-enoate (15) to form compound 16 in 78% yield. 13 At the last step, compound 16 was methylated in a two-phase reaction system to give the final product saflufenacil (1) in 86% yield.
In order to develop a practical process of preparing saflufenacil, a new synthetic route was designed, as shown in Scheme 3, and this is the subject of the present report. Compound 13 was obtained from 2 through four steps, in the manner of Liu. In our Scheme 1. A reported synthetic route for saflufenacil 1 (over-all yield < 10%). hands, 2-chloro-4-fluoro-5-nitrobenzoic acid (3) 9 was prepared in 96% yield (see Experimental section), and the catalytic hydrogenation reaction was carried out in a H 2 /Pd-C/MeOH system at 30 C and 0.2 MPa pressure in 98% yield. Subsequently, compound 16 was obtained in one step from compounds 13 and 5. This reduces the number of steps and avoids the use of methyl chloroformate. In the last step, compound 16 was methylated in a two-phase reaction system to give the final product saflufenacil (1) in 86% yield and 98.7% purity (HPLC).
In summary, an efficient and practical synthetic route for the preparation of saflufenacil (1) was developed starting with commercially available 2-chloro-4-fluorobenzoic acid (2). This route generated saflufenacil in high purity and 64.3% over-all yield on a kilogram scale. This new route is highly efficient and feasible for scale-up operations.

Experimental section
All solvents and reagents were purchased from commerical suppliers and used without further purification. Melting points were recorded on an RY-1 melting point apparatus and are uncorrected. 1 H NMR spectra were recorded on a Varian INOVA-400 spectrometer using TMS as an internal standard. Mass spectra were obtained from a Finnigan MAT-95/711 spectrometer. HPLC area percent was established on an Agilent 1100 liquid chromatography system with a Zorbax Eclipse Plus C18 column, 250 mm Â 4.6 mm (5 lm); k ¼ 254 nm; mobile phase: A (CH 3 OH) and B (H 2 O), 80:20 v/v. The HPLC analysis data is reported in area % and is not adjusted to weight %.

2-Chloro-4-fluoro-5-nitrobenzoic acid (3)
In a 20 L double layer glass reactor, 2-chloro-4-fluorobenzoic acid (1.00 kg, 5.73 mol) was slowly added to stirred concentrated sulfuric acid (4 L, 98%) and a clear solution was obtained. Next, 70% HNO 3 (0.80 kg, 8.90 mol) was added slowly into the solution in such a way that the temperature was kept below 30 C. The mixture was heated to 40-50 C and stirred for another 2 h. The reaction mixture was cooled to room temperature and poured into 10 L ice water and stirred for 0.5 h. The resulting solid was filtered under vacuum, washed with water (1.5 L Â 2), and dried at 45 C for 18 h to obtain 3 (1.21 kg, 96%) as an off-white solid, HPLC purity 99.5%; mp 148.9-149.6 C (lit. 148-151 C). 14

2-Chloro-4-fluoro-5-nitrobenzoyl chloride (11)
A suspension of 3 (1.10 kg, 5.00 mol) and thionyl chloride (3.5 L, 48.10 mol) was stirred and heated to reflux for 4 h. The thionyl chloride was removed under vacuum and 1.5 L toluene was added into the residue. The solvent was removed under vacuum again to remove the remaining thionyl chloride to obtain 11 (1.16 kg, 97%) as a light yellow oily liquid, which was dissolved in PhCl to use directly in the next step.

Saflufenacil (1)
A stirred suspension was prepared of 16 (1.22 kg, 2.50 mol) and tetrabutylammonium bromide (TBAB) (0.04 kg, 5 mol%) in toluene (3.8 L), tetrahydrofuran (1.8 L), and water (2.5 L) at room temperature. Dimethyl sulfate (0.33 kg, 2.63 mol) and 10% NaOH aqueous solution were added dropwise simultaneously, to keep the reaction solution pH ¼ 4-5. The reaction suspension was stirred for another 5 h. The mixture was allowed to stand and separate; the toluene layer was collected and washed with water (1 L Â 2) and dried over anhydrous Na 2 SO 4 . Most of the solvent was removed, heptane (2 L) was added, and the residue was stirred at room temperature for 2 h. The resulting solid was collected by suction filtration, washed with heptane (1 L), and dried at 40 C under vacuum to give 1 (1.08 kg, 86.1%.) as a white solid, HPLC purity 98.7%; mp 189.5-191.3 C, (lit. 188-191 C). 18