iodo(methoxy)methane

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

Procedure: Iodomethyl methyl ether (0.01 ml) is added to a solution of 34.0 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.5 ml of dry acetone, and the mixture is stirred in an argon atmosphere at room temperature for 10 min. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 42.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-methoxymethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a yellow oil. The solvent is removed by evaporation under reduced pressure The residue is purified by column chromatography on Sephadex

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

Procedure: Iodomethyl methyl ether (0.01 ml) is added to a solution of 34.0 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.5 ml of dry acetone, and the mixture is stirred in an argon atmosphere at room temperature for 10 min. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 42.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-methoxymethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a yellow oil. The solvent is removed by evaporation under reduced pressure The residue is purified by column chromatography on Sephadex

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35° C. for 5 min under nitrogen atmosphere then cooled to room temperature. Iodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35° C. for 3 h then cooled to room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silica cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification. then cooled to room temperature the resulting mixture was stirred at 35° C. for 3 h then cooled to room temperature The insoluble material was filtered off the filtrate was concentrated in vacuo The residue was dissolved in EtOAc the organic phase was washed with water dried over MgSO4 concentrated in vacuo Purification of the residue by SP4

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35° C. for 5 min under nitrogen atmosphere then cooled to room temperature. Iodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35° C. for 3 h then cooled to room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silica cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification. then cooled to room temperature the resulting mixture was stirred at 35° C. for 3 h then cooled to room temperature The insoluble material was filtered off the filtrate was concentrated in vacuo The residue was dissolved in EtOAc the organic phase was washed with water dried over MgSO4 concentrated in vacuo Purification of the residue by SP4

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

Procedure: In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.15 g), dimethylformamide (25 ml), and iodomethyl methyl ether (0.50 g), the title compound (0.26 g) was obtained as an amorphous solid, MS, m/z: 399.2(M+H)+, 797.2 (2M+H)+.

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

Procedure: Under a nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.4 mL, 1.0 mmol) to a solution of 7-(1-ethyl-propyl)-2,5-dimethyl-3-thiazol-5-yl-pyrazolo[1,5-a]pyrimidine (300 mg, 1.0 mmol) in THF (3 mL) at −78° C. Stir 30 min and add 1-iodomethyl methyl ether (205 mg, 1.2 mmol). Continue stirring for one hour and then slowly warm up to room temperature and stir overnight. Quench the reaction by adding saturated ammonium chloride solution and extract with ethyl acetate. Wash the organic layer with brine, dry over sodium sulfate, filter, and concentrate under vacuum to a residue. Purify the crude material by flash chromatography, eluting with hexanes/ethyl acetate (10/2) to give the title compound as a yellow foam (184 mg). MS (APCI) m/z 345.3 (M+1)+. Continue stirring for one hour stir overnight Quench the reaction extract with ethyl acetate Wash the organic layer with brine dry over sodium sulfate filter concentrate under vacuum to a residue Purify the crude material by flash chromatography eluting with hexanes/ethyl acetate (10/2)

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

Procedure: In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.15 g), dimethylformamide (25 ml), and iodomethyl methyl ether (0.50 g), the title compound (0.26 g) was obtained as an amorphous solid, MS, m/z: 399.2(M+H)+, 797.2 (2M+H)+.

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

Procedure: To 1.6 M n-BuLi in hexane (3.38 mL, 5.42 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (0.91 mL, 5.42 mmol) in anh. THF (10 mL) over 5 min. A solution of 3-(3-methoxy-phenyl)-1-methyl-azepan-2-one (as described in Example 4, Step A) (0.632 g, 2.71 mmol) in anhydrous THF (10 mL) was added and stirred OC for 1 h. Iodomethyl methyl ether (0.275 mL, 3.25 mmol) was added. After stirring for 30 min, the reaction was quenched with H2O, concentrated in vacuo, diluted with EtOAc, washed with 5N HCl (100 mL), water and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound. After stirring for 30 min the reaction was quenched with H2O concentrated in vacuo diluted with EtOAc washed with 5N HCl (100 mL), water and brine The organic layer was dried (MgSO4) concentrated

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

Procedure: To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and THF (3 mL) is added 1.34 M n-Bu-Li (0.50 mL, 0.80 mmol). After 30 minutes iodo-methoxy-methane (0.097 mL, 1.15 mmol) is added and the solution warmed to ambient temperature. After 1 hour the solution is diluted with EtOAc (40 mL) washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.12 g, 0.34 mmol, 44%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.72-1.90 (m, 4H), 2.09 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 3.28-3.37 (m, 1H), 3.44 (s, 3H), 4.61 (s, 2H), 6.65 (s, 1H), 6.93 (s, 1H). LC/MS (m/z): calcd. for C20H27N3OS (M+H)+: 358.3; found: 358.3. washed with water (30 mL), brine (30 mL) dried over MgSO4 filtered concentrated The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient)

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

Procedure: Iodomethyl methyl ether (0.01 ml) is added to a solution of 34.0 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.5 ml of dry acetone, and the mixture is stirred in an argon atmosphere at room temperature for 10 min. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 42.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-methoxymethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a yellow oil. The solvent is removed by evaporation under reduced pressure The residue is purified by column chromatography on Sephadex