Dimethyl 4-hydroxyphthalate

white solid

Preparation of dimethyl 4-hydroxyphthalate (‘1-2. To a solution of 4- hydroxyphthalic acid (20 g, 110 mmol) in CH3OH (100 mL) was added SOC12 (20 mL), The resulting solution was stirred at 80 °C for 4 hrs, The volatile was removed in vacuo to yield compound C1-2 as a white solid (23 g, yield: 99percent), which was used directly in the next step without further purification. ‘H NMR (CDCI3, 400 MHz) : 7.77(d, J = 8.8 Hz, lH), 7.03 (d, J 2 Hz, lH), 6.95 (dd, J 8.4 and 2.0 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H); MS (ESI): , n/z 21 l(M÷l).A solution of 4-hydroxyphthalic acid 1 (25.0 g, 137 mmol) in MeOH (700 mL) was charged with SOClA solution of 5 g (27.6 mmol) of 4-aminophthalic acid in 50 ml of 1M sulphuric acid is cooled to 0° C. and a solution of 2.27 g of sodium nitrite in 6 ml of water is then slowly added. After 15 minutes at 0° C., 15 ml of concentrated sulphuric acid are added and the mixture is heated at 100° C., with vigorous stirring, for 1 hour. At room temperature, the reaction medium is extracted with ethyl acetate and washed with water. After decantation, the organic phase is dried over magnesium sulphate and concentrated. The residue is purified on a silica column (dichloromethane 80-methanol 20). It is then dissolved in 100 ml of methanol and refluxed with 2 ml of acetic acid. After the disappearance of the diacid, the methanol is evaporated and the product is taken up in ethyl acetate and washed with water. [00350] M=5.2 g. Y=90percent. A solution of 4-hydroxyphthalic acid 16 (25.0 g, 137 mmol) in MeOH (500 mL) was charged with 6 N HCl in z4-hydroxyphthalic acid (50g, 274.5mmol) was dissolved in methanol (800mL) and cooled to 10°C. Sulfuric acid (134g, 1.37mol) was slowly added dropwise with stirring. After the addition was complete the reaction temperature was raised to 70°C overnight. Cooling to room temperature, it was concentrated in vacuo. It was extracted with ethyl acetate (700mL) and washed with water (500mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the product (32g, 55percent yield).To a solution of 4-hydroxyphthalic acid (1.04 g, 5.71 mmol) in MeOH (11.4 mL) was slowly added TMSCHN4-(2-Nitrophenoxy)phthalic acid dimethyl ester A mixture of Practical examples of particularly preferred phenol derivatives include phenol compounds such as p-phenyphenol, ... 3, 3'-dichloro-4, 4'-dihydroxydiphenyl sulfide, methyl-2, 2-bis(4'-hydroxyphenyl)acetate, n-butyl-4, 4-(4'-hydroxyphenyl)acetate, 4, 4'-thiobis(2-t-butyl-5-methylphenol), benzyl-p-hydroxybenzoate, chlorobenzyl-p-hydroxybenzoate, dimethyl-4-hydroxyphthalate, benzyl gallate, stearyl gallate, salicylic anilide, ...General procedure: General procedure for the preparation of 3 or 4-alkoxyphthalic anhydride (7a-7d, 9a-9d) Following a reported procedure [34], we added H2SO4 (0.054 mL, 1.02 mmol) to a stirred solution of 3- or 4-hydroxyphthalic acid (1.09 g, 6.00 mmol) in 12 mL of MeOH and the reaction was stirred at reflux overnight. Solvent was removed under reduced pressure and the solid residue obtained was dissolved in dichloromethane (40 mL) and washed with water (20 x 3 mL). The combined organic layer was dried over anhydr MgSO4, filtered and concentrated under reduced pressure to provide crude The compound prepared in step 1 above (0.47 g, 2.3 mmol) was dissolved in 4 ml of acetone, followed by stirring in the presence of K2CO3 (1.6 g, 11.3 mmol) at room temperature for 1 hour. Iodoethane (0.54 ml, 6.8 mmol) was added thereto, followed by stirring under reflux for overnight. The reaction mixture was filtered to remove K2CO3 and the solvent was eliminated under reduced pressure. After evaporating the solvent, the obtained product was purified by flash column chromatography. As a result, a target compound was obtained (0.44 g, 81%). 1H NMR (DMSO-d6, 500 MHz) delta 7.77 (d, J=8.3 Hz, 1H), 7.14-7.10 (m, 2H), 4.11 (q, J=6.9 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 1.33 (t, J=7.0 Hz, 3H). 13C NMR (DMSO-d6, 125 MHz) delta 167.9, 166.0, 161.1, 135.5, 131.4, 121.2, 116.2, 113.8, 63.9, 52.5, 52.2, 14.3.[00176] Preparation of A solution of 4-hydroxyphthalic acid 1 (25.0 g, 137 mmol) in MeOH (700 mL) was charged with SOCl2 (30.0 mL, 412 mmol) at 0 C. and stirred at room temperature for 20 h. The solvent was removed and the residue was partitioned between saturated aqueous NaHCO3 solution (100 mL) and CH2Cl2 (250 mL). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2*250 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to afford compound 2 (26.5 g, 92%) as a colorless oil: 1H NMR (400 MHz, CDCl3) delta 7.72 (d, J=8.5 Hz, 1H), 7.00 (d, J=2.6 Hz, 1H), 6.91 (dd, J=8.5, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H).A solution of 5 g (27.6 mmol) of 4-aminophthalic acid in 50 ml of 1M sulphuric acid is cooled to 0 C. and a solution of 2.27 g of sodium nitrite in 6 ml of water is then slowly added. After 15 minutes at 0 C., 15 ml of concentrated sulphuric acid are added and the mixture is heated at 100 C., with vigorous stirring, for 1 hour. At room temperature, the reaction medium is extracted with ethyl acetate and washed with water. After decantation, the organic phase is dried over magnesium sulphate and concentrated. The residue is purified on a silica column (dichloromethane 80-methanol 20). It is then dissolved in 100 ml of methanol and refluxed with 2 ml of acetic acid. After the disappearance of the diacid, the methanol is evaporated and the product is taken up in ethyl acetate and washed with water. [00350] M=5.2 g. Y=90%. 1H NMR (DMSO): 3.64 (3H, s), 3.67 (3H, s), 6.79-6.86 (2H, m), 7.56-7.60 (1H, d, J=8.4 Hz), 10.51 (1H, OH, s).A solution of 4-hydroxyphthalic acid 16 (25.0 g, 137 mmol) in MeOH (500 mL) was charged with 6 N HCl in z'-PrOH (46.0 mL, 274 mmol) at 0 C and refluxed for 24 h. The solvent was removed and the residue was partitioned between saturated aqueous NaHCC solution (100 mL) and EtOAc (250 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (2 chi 250 mL). The combined organic extracts were washed with brine, dried over Na2S04, and concentrated to afford compound 17 (25.0 g, 87%) as a brown color solid: NMR (400 MHz, (Chi, ) delta 7.72 id, ./ 8.5 Hz, 1 H), 7.00 (d, J = 2.6 Hz, H I ), 6.91 (dd, J = 8.5, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H).4-hydroxyphthalic acid (50g, 274.5mmol) was dissolved in methanol (800mL) and cooled to 10C. Sulfuric acid (134g, 1.37mol) was slowly added dropwise with stirring. After the addition was complete the reaction temperature was raised to 70C overnight. Cooling to room temperature, it was concentrated in vacuo. It was extracted with ethyl acetate (700mL) and washed with water (500mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the product (32g, 55% yield).Example 115: 1-(4-lsopropyl-phenyl)-7-prop-2-ynyloxy-isoquinoline-3-carboxylic acid ethyl ester ; EPO A solution of 5 g (27.6 mmol) of 4-aminophthalic acid in 50 mL of sulphuric acid (1 M) is cooled to 0 C. A solution of 2.27 g of sodium nitrite in 6 mL of water is then added slowly. After 15 minutes at 0 C., 15 mL of concentrated sulphuric acid are added and the mixture is maintained at 100 C. with vigorous stirring for 1 hour. At room temperature, the reaction medium is extracted with ethyl acetate and washed with water. After separation of the phases by settling, the organic phase is dried over magnesium sulphate and concentrated. The residue is purified on a column of silica (80 dichloromethane/20 methanol). It is then dissolved in 100 mL of methanol and refluxed with 2 mL of sulphuric acid. After disappearance of the diacid, the methanol is evaporated off and the product is taken up in ethyl acetate and washed with water. The organic phase is separated out after settling, dried over sodium sulphate and evaporated. [00140] M=5.2 g. Y=90%. 1H NMR (DMSO): 3.64 (3H, s), 3.67 (3H, s), 6.79-6.86 (2H, m), 7.56-7.60 (1H, d, J=8.4 Hz), 10.51 (1H, OH, s).General procedure: General procedure for the preparation of 3 or 4-alkoxyphthalic anhydride (7a-7d, 9a-9d) Following a reported procedure [34], we added H2SO4 (0.054 mL, 1.02 mmol) to a stirred solution of 3- or 4-hydroxyphthalic acid (1.09 g, 6.00 mmol) in 12 mL of MeOH and the reaction was stirred at reflux overnight. Solvent was removed under reduced pressure and the solid residue obtained was dissolved in dichloromethane (40 mL) and washed with water (20 x 3 mL). The combined organic layer was dried over anhydr MgSO4, filtered and concentrated under reduced pressure to provide crude 4-Hydroxyphthalic acid (1.09 g, 6.0 mmol) was dissolved in 12 ml of methanol. H2SO4 (0.054 ml, 1.02 mmol) was added thereto as a catalyst. The reaction mixture was stirred under reflux for overnight. The solvent was eliminated under reduced pressure, and the obtained solid was dissolved in dichloromethane, which was washed with water. The combined organic layer was dried over MgSO4, and the solvent was eliminated under reduced pressure. As a result, a crude target compound was obtained (1.20 g, 95%). 1H NMR (DMSO-d6, 500 MHz) delta 10.61 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.4, 2.5 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H). 13C NMR (DMSO-d6, 125 MHz) delta 168.3, 166.2, 160.8, 135.8, 131.7, 119.8, 117.1, 114.8, 52.5, 52.1.

Molecular Weight:210.18
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:210.05282342
Monoisotopic Mass:210.05282342
Topological Polar Surface Area:72.8
Heavy Atom Count:15
Complexity:250
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes