| 39% |
With N-Bromosuccinimide In tetrahydrofuran Irradiation; Reflux; |
|
| 33.1% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 85℃; for 5h; Inert atmosphere; |
1 1 Synthesis of l,2-bis(bromomethyl)-4-methoxybenzene (compound 2):
A mixture of 4-methoxy-l, 2-dimethylbenzene (50.0 g, 367 mmol), NBS (137 g, 771 mmol), and AIBN (1.21 g, 7.34 mmol) in CCl4 (600 mL) was refluxed for 5 h under N2. The resulting succinimide was removed by filtration, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (petroleum ether/dichloromethane = 8/1) to give the desired product (35.7 g, 367 mmol, 33.1 % yield) as a white solid. NMR: (400 MHz, CDCL3) δ: 7.31 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.4 2.8 Hz, 1H), 4.68 (s, 2H), 4.65 (s, 2H), 3.84 (s, 3H). |
| 32% |
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane Heating; |
|
| 29% |
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 15h; Heating; |
|
| 21% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4h; Heating / reflux; |
19.A
EXAMPLE 19; [0156] This example illustrates a preparation of 5-(5-methoxyisoindolin-2-yl)-l-methyl- lH-indole in an embodiment of the invention.; Step A: Synthesis of 1 ,2-bis(bromomethyl)-4-methoxybenzene as an intermediate ; [0157] To a mixture of 4-methoxy-l,2-dimethylbenzene (1.02 rnL, 7.34 mmol) in carbon tetrachloride (25 mL) was added N-bromosuccinimide (2.74 g, 15.4 mmol), followed by 2,2'- azobis(2-methylpropionitrile) (0.03 g, 0.18 mmol) and the mixture stirred at reflux for 4 h. After this time, the mixture was cooled to 50 0C, and the solids were removed by filtration. The filtrate was concentrated under reduced pressure and purification by flash chromatography (silica, 1 :99 ethyl acetate/hexanes) afforded 1 ,2-bis(bromomethyl)-4- methoxybenzene (0.46 g, 21%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, IH), 6.90 (d, J= 2.4 Hz, IH), 6.82 (dd, J= 2.4, 2.7, 8.4, 8.7 Hz, IH), 4.65 (s, 2H), 4.62 (s, 2H), 3.81 (s, 3H). |
| 19% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane Heating / reflux; |
86
(Intermediate Example 86) 5-Methoxy-2,3-dihydro-1H-isoindole 3,4-Dimethylanisole (3.0 g) was added to carbon tetrachloride, and N-bromosuccinimide (7.9 g) and 2,2'-azobisisobutyronitrile (50 mg) were added thereto and refluxed overnight. The reaction mixture was cooled to room temperature, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluding solvent; n-hexane: ethyl acetate 25: 1 → 20: 1) to give 1,2-bisbromomethyl-4-methoxybenzene (1.2 g, Y.: 19%). 1H NMR; (CDCl3) δ (ppm): 3.8 (3H, s), 4.6 (2H, s), 4.6 (2H, s), 6.8 (1H, dd), 6.9 (1H, d), 7.2 (1H, d). |
|
With N-Bromosuccinimide In dichloromethane for 0.666667h; Heating; irradiation; |
|
|
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 20h; Heating; |
|
|
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane Reflux; |
|
|
With N-Bromosuccinimide In tetrachloromethane for 20h; Heating / reflux; |
13
EXAMPLE 13. Synthesis of N-[2-(4-chlorophenyl)ethyl]-5-hydroxy-l,3-dihydro-2H- isoindole-2-carbothioamide (Res 12-83); The title compound was synthesized according to Scheme 9.N-bromosuccinimide Benzoyl peroxide I) HBr (48% In H2O), phenol, propionic acid2) HBr (48% in H2O)Res-12-83Scheme 9. Synthesis ofN-[2-(4-chlorophenyl)ethyl]-5~hydroxy-l,3-dihydro-2H-isoindole- 2-carbothioamide (Res-12-83) EPO Tosylamide Monosodium Salt (TsNHNa). To a stirred refluxing solution of freshly prepared NaOEt (1.0 eq.) in absolute EtOH was added tosylamide (1.0 eq.). The mixture was refluxed for 2 hours and then cooled. The insoluble TsNHNa was collected by filtration, washed with absolute ethanol and dried in vacuo.A mixture of 3,4-dimethylanisole (1), (1.0 eq.), N-bromosuccinimide (2.0 eq.) and benzoyl peroxide (cat.) was refluxed in CCl4 for 20 hours. After cooling, the insoluble material was filtered off and extracted with a small amount of CCl4. The filtrate and CCl4 used for the extraction were mixed and concentrated to give an oily residue containing 3,4-bis-(bromomethyl)anisole (2).To a stirred solution of TsNHNa (1.0 eq.) in anhydrous DMF at 8O0C was added dropwise under a N2 atmosphere .a solution of 2 (1.0 eq.) in DMF. The reaction mixture was stirred for 1 h. Then solid TsNHNa (1.0 eq.) was added at once and the mixture was stirred at 8O0C for 4 h. The reaction mixture was then concentrated and the solid residue was extracted with CHCl3. The organic phase was washed with IM NaOH, dried (MgSO4) and concentrated. The solid residue was washed with MeOH and dried under reduced pressure yielding 5-methoxy-2-tolylsulfonylisoindoline (3). Compound 3 (1.0 eq.), phenol (2.5 eq.) and propionic acid (0.5 eq.) were dissolved in HBr (48% in H2O), the mixture was refluxed for 4 hours under vigorous stirring under N2. The reaction solution was concentrated and HBr (48% in H2O) was added to the residue. The mixture was again refluxed under N2 for 3 hours. The reaction solution was cooled, and H2O and CHCl3 added. The water phase was separated and treated with active carbon. The water phase was then concentrated and the crystalline residue washed with diethylether to afford the hydrobromic salt of 5-hydroxyisoindoline (4).The amine 4 (1.0 eq.) was dissolved in anhydrous DMF and triethylamine (3.0 eq.) was added. This mixture was stirred for 15 minutes and then 2-(4-chlorophenyl)ethyl isothiocianate (1.2 eq.) was added. The mixture was stirred for additional 5 hours and then concentrated. The residue was dissolved in EtOAc and washed with water. The organic phase was dried (MgSO4) and concentrated to give the crude product, which was chromatographed on silicagel (heptane:EtOAc 8:2+l%AcOH) to afford Res-12-83 (31%). |
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