Methyl 3,5-dichloro-4-hydroxybenzoate

To a mixture of 4-hydroxybenzoic acid (0.2 g; 1 .3 mmol) and N-chlorosuccinimide (0.37 g; 2.76 mmol) in dry CHTo a mixture of bis(4-methoxy-3-iso-propylphenyl)iodonium tetrafluoroborate (4.55 g, 8.88 mmol) and copper powder (0.88 g, 13.80 mmol) in CH2Cl2 (40.0 mL) at 0 C. was added a solution of TEA (1.06 mL, 3.71 mmol) and To a mixture of bis (4-methoxy-3-iso-propylphenyl) iodonium tetrafluoroborate (4.55 g, 8.88 mmol) and copper powder (0.88 g, 13.80 mmol) inCH2CI2 (40.0 mL) at 0 C was added a solution of TEA (1.06 mL, 3.71 mmol) and methyl 3, 5-dichloro-4- hydroxybenzoate (1.65 g, 6.90 mmol) in dichloromethane (20.0 mL). The reaction mixture was stirred at room temperature for 3 d and filtered through a Celite plug. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 19) to afford methyl 3, 5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) benzoate as an orange oil (2.02 g, 80%): 'H NMR (300 MHz, DMSO-d6) :8 8.10 (m, 1 H), 6.85 (m, 2 H), 6.50 (m, 1 H), 3.90 (s, 3 H), 3.76 (s, 3H), 3.21 (m, 1 H), 1.14 (d, J= 6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3); Rf= 0.51.(a) Methyl 3, 5-dichloro-4-hydroxybenzoate (10 g) was coupled with bis(3-isopropyl-4-methoxyphenyl)iodonium tetrafluoroborate (35 g) using the method described in Example 1a. Purification by column chromatography (silica gel, 95:5 light petroleum ether/ethylacetate) followed by recrystallization from methanol gave 8.42 g (51%) of methyl 3, 5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-benzoate.3, 5-dichloro-4- hydroxybenzoic acid methyl ester (500 mg, 2.27 mmol) was dissolved in MeOH (15 mL). NH2NH2-H2O (5 mL) was added and the mixture was refluxed for 3 h. large amount of white solid was formed. After the reaction was completed (TLC), solvent and excess of hydrazine monohydrate were evaporated to dryness in vacuum. The crude product was obtained as a white solid (quantitative yield) and it was pure enough by NMR 1H to be used without further purification. 1H NMR (DMSO) delta: 6.50 (brs, 4H), 7.61 (s, 2H). 13C NMR (DMSO) delta: 112.91, 122.83, 126.76, 162.78, 165.52. MS m/z 221.0 (MH+, 100), 188.9 (M-NH-NH2, 96).a) 3, 5-Dichloro-4-hydroxybenzoic acid hydrazide A mixture of 10.0 g (a) 3, 5-Dichloro-4-hydroxybenzoic acid hydrazide. A mixture of 10.0 g To a mixture of 4-hydroxybenzoic acid (0.2 g; 1 .3 mmol) and N-chlorosuccinimide (0.37 g; 2.76 mmol) in dry CH2CI2 (15 ml) TiCI_4 (0.1 ml; 0.9 mmol) was added at room temperature and the resulting mixture was stirred for 5h. To it ice (-10 g) was added and the resulting slurry was stirred for 30 min at room temperature, diluted to 100 ml with EtOAc. The organic phase was washed with H20 (2 x 10 ml), brine (10 ml), dried over anhydrous MgS04, filtered and the filtrate evaporated to dryness, The residue was purified by FCC (Si02, CH2CI2) to give the title compound (0.19 g; 65%), as colourless solid. 1 H-NMR (CDCI3) 7.96 s, 2H) ; 6.18 (s, 1 H): 3.89 (s, 3H).[0246] 62.1 g (0.30 mol) of 4-hydroxy-3, 5-dichlorobenzoic acid was dissolved in 300 mL of methanol. 3 g of p-toluenesulfonic acid was added. The reaction mixture was heated and refluxed for 6 hours. The solvent was removed under reduced pressure. The residue was dissolved in 500 mL of dichloromethane, washed with water three times (200 mL3), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was removed to obtain 56.3 g of the target product with a yield of 84.9%. m/z 219.01(M-H).[0247] 56 g (0.253 mol) of (a) was dissolved in 300 mL of methanol, cooled in an ice bath. 15.13 g (0.40 mol) of sodium borohydride were added in batches, and the addition was completed within about 1.5 hours. The reaction was continued with stirring for 2 hours, thin layer detection showed that the raw materials were reacted completely. The solvent was removed under reduced pressure. The residue was dissolved in water which is adjusted to be with the pH of 2 by adding 2M hydrochloric acid. The solution was extracted with dichloromethane three times (200 mL3). The extracts were combined, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was removed under reduced pressure, and the residue was crystallized with dichloromethane and petroleum ether (1/5). 30.3g of the target compound was obtained in 62.0% yield. m/z 192.02(M-H).

Molecular Weight:221.03
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:219.9693994
Monoisotopic Mass:219.9693994
Topological Polar Surface Area:46.5
Heavy Atom Count:13
Complexity:186
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes