1-bromo-1-chloropropane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxy benzyl alcohol CAS NO. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2 H, J=8.8 Hz), 6.88 (d, 2 H, J=8.8 Hz), 5.03 (t, 1 H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2 H, J=6.1 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS eI m/z 200. was refluxed for 2 hours The solution was cooled filtered the filtrate concentrated washed with water, brine dried over magnesium sulfate The material was chromatographed on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-acetamidophenol (182.2 g, 1.2 moles), bromochloropropane (157.4 g, 1.0 mole), and potassium carbonate (145.0 g, 1.05 moles) was refluxed overnight in 700 ml of acetone. The acetone solution formed white crystals after being placed in a refrigerator overnight. The solution was filtered and the crystals washed with acetone. The filtrate was stripped to dryness, and the residue dissolved in chloroform and extracted with a 5% sodium hydroxide solution. Removal of the chloroform gave an oil. The white crystals obtained earlier were also dissolved in chloroform and extracted with a 5% sodium hydroxide solution. Removal of the chloroform gave a white solid. The white solid and oil were combined with acetone and placed in a refrigerator; white crystals were obtained. A 5-g sample of the white solid was recrystallized from acetone a second time to furnish 1.76 g (after drying in vacuo overnight at 80° C.) (23% yield) of white crystalline product, m.p. 125°-127° C. after being placed in a refrigerator overnight The solution was filtered the crystals washed with acetone the residue dissolved in chloroform extracted with a 5% sodium hydroxide solution Removal of the chloroform gave an oil The white crystals obtained earlier extracted with a 5% sodium hydroxide solution Removal of the chloroform gave a white solid white crystals were obtained A 5-g sample of the white solid was recrystallized from acetone a second time to furnish

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-[3-(4-amino-3-hydroxybenzoyl)indol-1-yl]butanoate (30 g) was suspended in acetone (390 ml), potassium carbonate (23.8 g) and chlorobromopropane (24 ml) were added to the suspension. The mixture was stirred at room temperature for four hours. The reaction mixture was cooled and filtrated. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 22.8 g of ethyl 4-{3-[4-amino-3-(3-chloropropoxy)benzoyl]indol-1-yl}butanoate as colorless prisms. The reaction mixture was cooled filtrated The filtrate was concentrated under reduced pressure The resultant residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-{3-[4-(4-ethylphenyl)methylamino-3-hydroxybenzoyl]indol-1-yl}butanoate (39.3 g) was dissolved in N,N-dimethylformamide (200 ml), and potassium carbonate (22.4 g) and chlorobromopropane (24 ml) were added to the solution. The mixture was stirred at room temperature for four hours. The reaction mixture was poured into water, and ethyl acetate was further added for extraction. The formed organic layer was sequentially washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine, and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby obtain 44.8 g of ethyl 4-{3-[3-chloropropoxy-4-(4-ethylphenyl)methylaminobenzoyl]indol-1-yl}butanoate as a yellow oil. MS(m/z): 562(MH+); IR(CHCl3)cm−1:3450, 1730, 1595; NMR(CDCl3)δ:1.21(t, 3H), 1.25(t, 3H), 2.13˜2.36(m, 6H), 2.66(q, 2H), 3.72(t, 2H), 4.10(q, 2H), 4.21˜4.31(m, 4H), 4.43(d, 2H), 5.03(t, 1H), 6.59(d, 1H), 7.08˜7.50(m, 9H), 7.60(s, 1H), 8.31˜8.37(m, 1H). was further added for extraction The formed organic layer was sequentially washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine dried The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-{3-[4-(4-ethylphenyl)methylamino-3-hydroxybenzoyl]indol-1-yl}butanoate (39.3 g) was dissolved in N,N-dimethylformamide (200 ml), and potassium carbonate (22.4 g) and chlorobromopropane (24 ml) were added to the solution. The mixture was stirred at room temperature for four hours. The reaction mixture was poured into water, and ethyl acetate was further added for extraction. The formed organic layer was sequentially washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine, and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby obtain 44.8 g of ethyl 4-{3-[3-chloropropoxy-4-(4-ethylphenyl)methylaminobenzoyl]indol-1-yl}butanoate as a yellow oil. MS(m/z): 562(MH+); IR(CHCl3)cm−1:3450, 1730, 1595; NMR(CDCl3)δ:1.21(t, 3H), 1.25(t, 3H), 2.13˜2.36(m, 6H), 2.66(q, 2H), 3.72(t, 2H), 4.10(q, 2H), 4.21˜4.31(m, 4H), 4.43(d, 2H), 5.03(t, 1H), 6.59(d, 1H), 7.08˜7.50(m, 9H), 7.60(s, 1H), 8.31˜8.37(m, 1H). was further added for extraction The formed organic layer was sequentially washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine dried The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.646 ml (5.181 mmol) of 1-bromo-chloropropane, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 206 mg (0.4454 mmol, 86%) of 2-(3-chloropropoxy-2' -hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.8-2.2 (6H, m, 3CH2), 2.36 (4H, t, 2CH2), 2.5-2.8 (4H, m, 2CH2), 3.51 (2H, t, CH2), 3.66 (6H, s, 2CH3), 4.16 (2H, t, CH2), 6.05 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 461 (M-H)- The reaction mixture was filtered by suction through Celite to remove the solid matter the filtrate was washed with ethyl acetate After the solvent in the filtrate was evaporated off under reduced pressure the evaporated residue was dissolved in chloroform This solution was washed with dilute hydrochloric sodium chloride solution in this sequence was dried by adding anhydrous sodium sulfate The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2 H, J=8.8 Hz), 6.88 (d, 2 H, J=8.8 Hz), 5.03 (t, 1 H, J=5.7 Hz), 4.40 (d, 2 H, J=5.5 Hz), 4.05 (t, 2 H, J=6.1 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS eI m/z 200. was refluxed for 2 hours The solution was cooled filtered the filtrate concentrated washed with water, brine dried over magnesium sulfate The material was chromatographed on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxy benzyl alcohol CAS No. [623–05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.03 (t, 1H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2H, J=6.1 Hz), 3.77 (t, 2H, J=6.4 Hz); MS eI m/z 200. was refluxed for 2 hours The solution was cooled filtered the filtrate concentrated washed with water, brine dried over magnesium sulfate The material was chromatographed on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl octahydro-2,7-naphthyridine-2(1H)-carboxylate (320 mg, 1.33 mmol, 1 eq), chloro bromopropane (530 mg, 3.33 mmol, 2.5 eq) and K2CO3 (736 mg, 5.33 mmol, 4 eq) in acetone (25 mL) was heated to reflux overnight, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow oil (190 mg, 47%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 317.2 (M+1). was heated to reflux overnight filtered The filtrate was concentrated in vacuo the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g , 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.03 (t, 1H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2H, J=6.1 Hz), 3.77 (t, 2H, J=6.4 Hz); MS eI m/z 200. was refluxed for 2 hours The solution was cooled filtered the filtrate concentrated washed with water, brine dried over magnesium sulfate The material was chromatographed on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2 H, J=8.8 Hz), 6.88 (d, 2 H, J=8.8 Hz), 5.03 (t, 1 H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2 H, J=6.1 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS eI m/z 200. was refluxed for 2 hours The solution was cooled filtered the filtrate concentrated washed with water, brine dried over magnesium sulfate The material was chromatographed on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2 H, J=8.8 Hz), 6.88 (d, 2 H, J=8.8 Hz), 5.03 (t, 1 H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2 H, J=6.1 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS eI m/z 200. was refluxed for 2 hours The solution was cooled filtered the filtrate concentrated washed with water, brine dried over magnesium sulfate The material was chromatographed on silica gel