N,N-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine

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:

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: N,N-dimethylformamide di-tert-butyl acetal (134 mg, 0.66 mmol) was added to a solution of 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyric acid (90 mg, 0.22 mmol) in toluene (2.5 ml) at 90° C. The reaction was stired for 3 h and concentrated to give tert-butyl 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyric acid that was used in the next step with no further purification. concentrated

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

Procedure: A solution of methyl 4-[5-[2-carboxy-1-hydroxy-3-(propylcarbamoyl)propyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.81 g), and N,N-dimethylformamide di-tert-butyl acetal (1.54 ml, redistilled) in methylene chloride (26 ml) was stirred under a nitrogen atmosphere for 1 hour. The solvent was evaporated, and the product purified by flash chromatography, eluting with 4:1 ethyl acetate: hexane, to give methyl 3-methoxy-4-[1-propyl-5-[3-(propylcarbamoyl)prop-1-enyl]indol-3-ylmethyl]benzoate (0.56 g, 79%, as a separable mixture of olefin isomers) as a white solid: mp 140°-142°; E-olefin partial NMR (300 MHz, DMSO-d6): 0.83(m, 6H, 2×CH3), 3.82(s, 3H, OCH3), 3.92(s, 3H, OCH3). 6.15(d of t, 1H, olefinic-H), 6.47(d, J=15.9 Hz, 1H, olefinic-H), 7.86(t, 1H, NH), Z-olefin partial NMR (300 MHz, DMSO-d6 ): 0.82(m, 6H, 2×CH3), 3.82(s, 3H, OCH3), 3.90(s, 3H, OCH3), 5.70(m, 1H, olefinic-H), 6.57(d, J=11.5 HZ, 1H, olefinic-H), 7.86(t, 1H, NH). The solvent was evaporated the product purified by flash chromatography eluting with 4:1 ethyl acetate

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

Procedure: A mixture of methyl 4-[5-(1-hydroxyallyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.57 g, prepared as described in Example 87, part a), N,N-dimethylformamide di-tert-butylacetal (1.63 g, redistilled) in dry xylene (15 ml), under an atmosphere of nitrogen, was stirred and heated under reflux for 2 hr. A further portion of the acetal (1.63 g) was added, and refluxing continued for a further 3.5 hr. The cooled solution was introduced directly into a column of silica gel and the product purified by flash chromatography, eluting with 7:3 ethyl acetate:hexane, to give methyl E-4-[5-[4-(dimethylamino)-4-oxobut-1-enyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.71 g, 40%) as an off-white solid: mp 122.5°-123.5°; partial NMR (300 MHz, DMSO-d6): 0.81(t, 3H, CH2CH3), 1.75(m, 2H, CH2CH3), 2.83(s, 3H, NCH3), 3.01(s, 3H, NCH3), 3.24(d, 2H, --COCH2CH=), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.05(s, 4H, ArCH2Ar', NCH2CH2), 6.15(d of t, 1H, CH2CH=CH), 6.45(d, 1H, CH2CH=CH). prepared heated under reflux for 2 hr refluxing The cooled solution was introduced directly into a column of silica gel the product purified by flash chromatography eluting with 7:3 ethyl acetate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 125 mL, single-neck, round-bottomed flask was charged with di-tert-butoxy-N,N-dimethylmethanamine (48.2 ml, 201 mmol), 3-chloro-2,4-difluorobenzoic acid (9.67 g, 50.2 mmol), and DMF (50 ml). The reaction was heated to 80° C. for 48 hours. After cooling to ambient temperature, the reaction was diluted with saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaHCO3 and brine, dried, filtered and concentrated to provide the desired product as a gold oil. After cooling to ambient temperature The aqueous phase was extracted with EtOAc the combined organic phases were washed with saturated NaHCO3 and brine dried filtered concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 125 mL, single-neck, round-bottomed flask was charged with di-tert-butoxy-N,N-dimethylmethanamine (48.2 ml, 201 mmol), 3-chloro-2,4-difluorobenzoic acid (9.67 g, 50.2 mmol), and DMF (50 ml). The reaction was heated to 80° C. for 48 hours. After cooling to ambient temperature, the reaction was diluted with saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaHCO3 and brine, dried, filtered and concentrated to provide the desired product as a gold oil. After cooling to ambient temperature The aqueous phase was extracted with EtOAc the combined organic phases were washed with saturated NaHCO3 and brine dried filtered concentrated

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

Procedure: 0.96 ml of N,N-dimethylformamide di-t-butyl acetal was added dropwise within 20 minutes to a boiling solution of 0.34 g of 4,5-dihydro-7-oxo-8-(m-fluorophenyl)-7H-thieno[2,3-a]quinolizine-10-carboxylic acid in 5 ml of toluene. The mixture was heated under reflux for an additional 30 minutes, left to stand at room temperature overnight and then washed once with water, twice with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate and there was obtained tert-butyl 8-(m-fluorophenyl)-4,5-dihydro-7-oxo-7H-thieno[2,3-a ]quinolizine-10-carboxylate of m.p. 135°-137°. The mixture was heated under reflux for an additional 30 minutes left washed once with water, twice with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution The organic phase was dried over sodium sulfate evaporated in vacuo The residue was recrystallized from ethyl acetate