1-bromo-4-methoxybutane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a suspension of 3.9 g. (0.16 mole) of magnesium turnings in 300 ml. of dry ether was added dropwise 26.7 g. (0.16 mole) of 1-bromo-4-methoxybutane in 80 ml. of ether and the mixture refluxed for four hours. The reaction mixture was cooled and 14.6 g. (0.008 mole) of benzophenone in 100 ml. of dry ether was added dropwise. The mixture was stirred at ambient temperature for 18 hours, cautiously quenched with water and the ether layer separated. The aqueous layer was extracted with ether and the combined ether extract was dried and concentrated to give 1,1-diphenyl-5-methoxy-1-pentanol, m.p. 112°-115° C. To a suspension of 3.9 g The reaction mixture was cooled cautiously quenched with water the ether layer separated The aqueous layer was extracted with ether the combined ether extract was dried concentrated

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

Procedure: Scheme 6 illustrates the synthesis of N-ethyl phenazine 1-hydroxybutyl methyl ether. The phenazine ether (21) is prepared by the alkylation of the 1-hydroxyphenazine (1) with 4-methoxybutylbromide (Aldrich Chemical Company, USA) to give phenazine derivative (21). N-ethyl phenazine (22) is prepared by reaction of compound (21) with diethyl sulfate in the presence of potassium carbonate.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Scheme 6 illustrates the synthesis of N-ethyl phenazine 1-hydroxybutyl methyl ether. The phenazine ether (21) is prepared by the alkylation of the 1-hydroxyphenazine (1) with 4-methoxybutylbromide (Aldrich Chemical Company, USA) to give phenazine derivative (21). N-ethyl phenazine (22) is prepared by reaction of compound (21) with diethyl sulfate in the presence of potassium carbonate.

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 1-bromo-4-methoxybutane to replace 1-bromopentane, 1′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (93%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.30-6.86 (m, 4H), 6.45 (s, 1H), 6.18 (s, 1H), 4.72 (ABq, 2H), 4.18-4.04 (m, 4H), 3.88-3.63 (m, 2H), 3.44-3.37 (m, 2H), 3.30 (s, 3H), 1.88-1.56 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.3, 138.2, 132.5, 128.8, 123.9, 123.1, 121.1, 111.4, 108.6, 99.3, 80.1, 72.0, 64.5, 63.9, 58.6, 57.9, 40.0, 26.9, 24.3; MS (ES+) m/z 381.9 (M+1).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ether (60 ml) and 4-bromo-1-methoxy-butane (10.2 g) were added to magnesium turnings (1.46 g). After formation of the Grignard reagent, the mixture was cooled to 0° and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° C. for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml) and the mixture was stirred for a further 20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound or the free base (3.55 g), m.p. 128°-139° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 178°-179° C. the mixture was stirred for a further 20 minutes The mixture was concentrated in vacuo the aqueous residue extracted with chloroform (3×100 ml) The extracts were dried (Na2SO4) concentrated in vacuo Ether (20 ml) was added the product was filtered recrystallised from ethyl acetate

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

Procedure: A Grignard reagent was prepared from 4-methoxybutyl bromide (5 g) and magnesium (0.72 g) in dry ether (25 ml). After cooling with an ice-bath, under a blanket of nitrogen, a solution of 8-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (2.2 g) in dichloromethane (25 ml) was added slowly. When addition was complete the mixture was stirred at room temperature for 3 hours. It was poured onto saturated aqueous NH4Cl, the layers were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with water and dried (MgSO4). Filtration and evaporation gave an orange solid, which was triturated with boiling ethyl acetate, cooled, filtered and the crystals were washed with hexane. The crystals were suspended in boiling ethanol and acidified with ethanolic HCl. Evaporation of the solution gave a solid which crystallised from isopropanol. Two crops were combined and dried at 50°/1 mm to give pure 8-chloro-10-hydroxy-10-(4-methoxybutyl)-2,3,4,10-tetrahydropyrimido[1,2-a]indole, hydrochloride quarter hydrate (2.28 g) as buff-cream crystals, m.p. 218°-221° (dec). After cooling with an ice-bath, under a blanket of nitrogen When addition the layers were separated the aqueous phase extracted with dichloromethane The combined organic phases were washed with water dried (MgSO4) Filtration and evaporation gave an orange solid, which was triturated with boiling ethyl acetate cooled filtered the crystals were washed with hexane Evaporation of the solution gave a solid which crystallised from isopropanol dried at 50°/1 mm