General procedure for the synthesis of 4-chloro-3-fluoro-2-iodoaniline from tert-butyl (4-chloro-3-fluoro-2-iodophenyl)carbamate:
1. Compound 103 (110.0 g, 0.296 mol) was added to a 3L four-necked round-bottomed flask equipped with an overhead stirrer, a reflux condenser, a water bath, a 250 ml dosing funnel, an internal temperature probe, and an argon inlet.
2. Ethanol (900 ml) was added to the flask and the mixture was cooled to 50°C.
3. Hydrochloric acid (37%, 145.9 ml) was added slowly and dropwise, controlling the internal temperature to below 15°C.
4. the reaction mixture was heated to 50-55 °C and maintained for 2 h. The complete conversion of the feedstock (Rt 6.73 min) to the product (Rt 5.44 min) was subsequently confirmed by analysis by HPLC method (Test 20, MeOH).
5. The reaction solution was cooled to 50°C and NaOH solution (80.0 g dissolved in 1000 ml of water, 865 ml added) was added stepwise, keeping the temperature below 150°C and monitoring the pH to neutral.
6. Transfer the mixture to a single neck flask and store at 4°C for 15 hrs.
7. concentrated under vacuum at 35 °C to remove a total of 970 ml of distillate to give a colorless solution containing precipitated solids.
8. The slurry was cooled to 40 °C and kept for 1 h. The solids were subsequently vacuum filtered and washed with ethanol:water (1:4, 200 ml) at 4 °C.
9. After vacuum drying at 35 °C for 72 h, the impure compound 104 (80 g, 99% yield, 95% purity at 254 nm) was obtained.
10. The solid was dissolved in hot (60°C) ethanol (450 ml) and filtered while hot to remove insoluble fines.
11. The filtrate was concentrated under vacuum to 175 ml at 35 °C, followed by slow dropwise addition of water (70 ml) over 3-4 hours, slow cooling to 40 °C and continued stirring for 0.5 hours.
12. Vacuum filtration, washing with ethanol:water (3:2, 100 ml) at 40 °C and vacuum drying at 35 °C gave compound 104 as orange colored needle-like crystals (70.5 g, 88% yield, 98% purity at 272 nm).
13. The second batch of product was recovered from the mother liquor as a light yellow solid (4.6 g, 5% yield, 98% purity at 272 nm).
14. The two batches were combined to give a total yield of 93%.
Physicochemical properties of compound 104:
- Molecular Formula: C6H4ClFIN
- Molecular weight: 271.45 g/mol
- HPLC analysis (test 20, MeCN): Rt 5.44min; 98% purity at 272nm
- Melting point: 80.5-81°C
- ESI+ MS: m/z 271.9 [M+H]+ (65%); 312.9 [M+MeCN+H]+ (100%)
- 1H NMR (400 MHz, d6-DMSO): δ 5.69 (2H, s, 2xN-H), 6.55 (1H, d, Ar-H), 7.18 (1H, t, Ar-H)
- 13C NMR (100 MHz, d6-DMSO): δ 70.97, 71.24 (CI), 104.03, 104.25 (C-Cl), 110.14, 110.17 (CH), 129.90 (CH), 150.09, 150.14 (CN), 155.45, 157.82 (CF)
- 19F NMR (376 MHz, d6-DMSO): δ -91.60 (1F, d)
