2-(diethylamino)acetic acid

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 gm of ethyl-3-(3-diethylamino-propyl)-carbodiimide was added to a suspension of 555 mgm of 2,6-diamino-benzo[1,2-d:5,4-d']bisthiazole and 655 mgm of N,N-diethyl-glycine in 20 ml of methylene chloride, and the mixture was stirred overnight at room temperature. After adding water and filtering off the precipitate, the methylene chloride phase was separated, dried, concentrated and chromatographed on a dry 10 gm-silicagel column with chloroform as the mobile phase. The title compound was collected in the first fractions and converted into the dihydrochloride by treatment with ethereal hydrochloric acid. filtering off the precipitate the methylene chloride phase was separated dried concentrated chromatographed on a dry 10 gm-silicagel column with chloroform as the mobile phase The title compound was collected in the first fractions

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 gm of ethyl-3-(3-diethylamino-propyl)-carbodiimide was added to a suspension of 555 mgm of 2,6-diamino-benzo[1,2-d:5,4-d']bisthiazole and 655 mgm of N,N-diethyl-glycine in 20 ml of methylene chloride, and the mixture was stirred overnight at room temperature. After adding water and filtering off the precipitate, the methylene chloride phase was separated, dried, concentrated and chromatographed on a dry 10 gm-silicagel column with chloroform as the mobile phase. The title compound was collected in the first fractions and converted into the dihydrochloride by treatment with ethereal hydrochloric acid. filtering off the precipitate the methylene chloride phase was separated dried concentrated chromatographed on a dry 10 gm-silicagel column with chloroform as the mobile phase The title compound was collected in the first fractions

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Powdery solid N,N-diethylglycine sodium salt (produced by Tokyo Kasei Kogyo K.K. Japan) was dissolved in deionized water. The solubility in water of the N,N-diethylglycine sodium salt was 34% by mass (20° C.). To 342 g of this aqueous 34% by mass solution, was added 98% by mass sulfuric acid to adjust the pH to 6.6. This aqueous solution was condensed at 90° C. under a reduced pressure until the N,N-diethylglycine sodium salt concentration in the solution reached 67% by mass. The condensed solution was cooled to 40° C. and was stirred for one hour. The deposited crystalline sodium sulfate was removed at 40° C. by using a Buchner vacuum filter. Thereby, an aqueous 67% by mass solution of N,N-diethylglycine was obtained in an amount of 125 g. The aqueous N,N-diethylglycine solution contained sodium sulfate at a concentration of 0.9% by mass. 34% by mass (20° C.) condensed at 90° C. under a reduced pressure until the N,N-diethylglycine sodium salt concentration in the solution The deposited crystalline sodium sulfate was removed at 40° C. filter

反応条件: temp:3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diethylamine (9.5 L) was charged into a 20 L glass-lined reactor and cooled to 3° C. Chloroacetic acid (1.21 kg) in MTBE (1.8 L) was added over 1 hour with cooling—the temperature rose to 16° C. during the addition. The mixture was warmed to 20° C., stirred over night and concentrated on rotary evaporator giving yellow oil. This oil was re-concentrated with iPrOAc, mixed with iPrOAc (4.5 L) and stirred over night. The off-white hygroscopic precipitate was filtered, washed with iPrOAc (1.5 L) and immediately placed into a drying cabinet to avoid deliquescence. After drying, titled product was obtained (820 g, Y=49%). rose to 16° C. during the addition The mixture was warmed to 20° C. concentrated on rotary evaporator giving yellow oil This oil was re-concentrated with iPrOAc mixed with iPrOAc (4.5 L) stirred over night The off-white hygroscopic precipitate was filtered washed with iPrOAc (1.5 L) After drying

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of chloroacetic acid (30 g, 0.32 mol) in diethylamine (230 mL, 2.2 mol) was stirred overnight. The obtained white precipitate was removed by filtration. The filtrate was evaporated to dryness to afford yellow oil to which EtOAc (300 mL) was added. The obtained precipitate was again removed by filtration. The filtrate was evaporated to afford yellow solid residue (44 g) that was washed with hexane (2×100 mL), EtOAc (2×50 mL) and again with hexane (50 mL), and then dried in vacuo to afford title Intermediate 2 (38 g). The obtained white precipitate was removed by filtration The filtrate was evaporated to dryness to afford yellow oil to which EtOAc (300 mL) was added The obtained precipitate was again removed by filtration The filtrate was evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and N,N-diethylaminoacetic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-2-diethylamino-ethanone. MS (M+H)+: 459.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and N,N-diethylaminoacetic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-2-diethylamino-ethanone. MS (M+H)+: 459.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 gm of ethyl-3-(3-diethylamino-propyl)-carbodiimide was added to a suspension of 555 mgm of 2,6-diamino-benzo[1,2-d:5,4-d']bisthiazole and 655 mgm of N,N-diethyl-glycine in 20 ml of methylene chloride, and the mixture was stirred overnight at room temperature. After adding water and filtering off the precipitate, the methylene chloride phase was separated, dried, concentrated and chromatographed on a dry 10 gm-silicagel column with chloroform as the mobile phase. The title compound was collected in the first fractions and converted into the dihydrochloride by treatment with ethereal hydrochloric acid. filtering off the precipitate the methylene chloride phase was separated dried concentrated chromatographed on a dry 10 gm-silicagel column with chloroform as the mobile phase The title compound was collected in the first fractions