| 83.1% |
Stage #1: With N-benzyl-N,N,N-triethylammonium chloride; potassium hydroxide In ethanol for 3 h; Reflux; Large scale
Stage #2: With hydrogenchloride In waterLarge scale |
The intermediate I (3.2 kg, 10 . 2mol) and 34gTEBA into ethanol, stirring, by adding potassium hydroxide (1.2 kg, 21 . 4mol), heating reflow 3h, evaporate the ethanol, the residue for adding 20L water-soluble. Acidification with concentrated HCl to pH=1-2, generating a large amount of a buff solid, filtered, the filter cake is washed with water to neutral, buff solid obtained after drying 2.42 kg, II as intermediate, yield: 83.1percent. |
| 81.2% |
Stage #1: at 65℃; for 2 h;
Stage #2: With water; acetic acid In methanol at 60℃; for 2 h; |
Example 2 Production of (11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-yl)acetic acid The total amount of methyl 2-(4-methoxycarbonylmethylphenoxymethyl)benzoate obtained in Example 1 was charged in a 4-neck flask, to which 150 ml of methanol and a solution of 17.0 g of sodium hydroxide dissolved in 100 ml of water were added, for agitation at 65°C for 2 hours. After the reaction mixture was cooled to room temperature (about 25°C), the reaction mixture was diluted with 200 ml of water, to which 2.0 g of active charcoal was added for agitation at room temperature for one hour. Subsequently, the resulting mixture was filtered through a Buchner funnel to remove the active charcoal. The active charcoal was washed on the Buchner funnel with 100 ml of water. The filtrate was combined with the wash water, which was then heated to 60°C. A solution of 26.5g of acetic acid dissolved in 50 ml of water was dropwise added to the heated solution over 2 hours, for depositing a crystal at the same temperature. After the solution was cooled to 10°C, then, the crystal was collected by filtration with a Buchner funnel, and washed with 200 ml of water. The crystal after washing was dried under reduced pressure, to obtain 46.5 g (0.1624 mole) of 2-(4-carboxymethylphenoxymethyl)benzoic acid. The yield (the yield from 4-hydroxyphenylacetic acid in Example 1) was 81.2 percent. 1H NMR(400MHz,DMSO-d6) δ 3.47(s,2H), 5.45(s,2H), 6.90(d,J=8.0Hz,2H), 7.16(d,J=8.4Hz,2H), 7.47(t,J=7.6Hz,1H), 7.36(t,J=7.4Hz,1H), 7.57(d,J=7.2,1H), 7.86(d,J=7.6,1H) The total amount of the 2-(4-carboxymethylphenoxymethyl)benzoic acid obtained above and 200 ml of chlorobenzene were charged in a 500-ml 4-neck flask, to which 75.0 g (0.3753 mole) of trifluoroacetic anhydride was added, for subsequent agitation at about 20°C for 4 hours. After adding 2.3 g (0.0162 mole) of BF3-ether complex at -10 to 0°C over 10 minutes, agitation was done for another 30 minutes to separate the liquid layers. The resulting organic layer was washed with 200 ml of water. After the organic layer was added to a solution of 7.2 g of sodium hydroxide dissolved in 300 ml of water for agitation for 30 minutes, phase separation was done. 2.0 g of active charcoal was added to the resulting separated aqueous layer for agitation for 30 minutes; and the active charcoal was separated by filtration with a Buchner funnel. The resulting active charcoal was washed with 10 ml of water on the Buchner funnel. The filtrate and the wash water were combined together, and the resulting mixture was retained at about 40°C. To the mixture was dropwise added a mix solution of 11.3 g (0.1876 mole) of acetic acid and 50 ml of water, over 30 minutes. After completion of dropwise addition, the resulting mixture was cooled to 0 to 10°C, and filtered with a Buchner funnel to collect the deposited crystal, which was further washed with 200 ml of water. The crystal after washing was dried under reduced pressure, to obtain the entitled compound of 42.0 g. The yield [the yield from 2-(4-carboxymethylphenoxymethyl)benzoic acid] was 96.4 percent, at a purity of 99.9 percent as determined by HPLC. (HPLC conditions) Column: Inertsil ODS-5 μm (4.6 mm ID x 15 cm) Mobile phase: 0.02 percent of aqueous trifluoroacetic acid solution/acetonitrile = 5/5 --> 3/7 (30 minutes) Detection wavelength: UV 254 nm 1H NMR(400MHz,DMSO-d6) δ 3.63(s,2H), 5.30(s,2H), 7.07(d,J=8.0Hz,2H), 7.48(t,J=3.6Hz,1H), 7.55(d-d,J=7.9Hz,2H), 7.67(t,J=7.6Hz,1H), 7.78(d,J=7.6Hz,1H), 7.97(d,J=2.0Hz,1H) |
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