4-chloro-1-isothiocyanato-2-methylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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: A mixture of 4-chloro-2-methylphenyl-isothiocyanate (12.8 g), N-methyl aminooxy acetic acid hydrochloride (10 g), triethylamine (7.5 g) and chloroform (100 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (200 mL) and extracted with sodium bicarbonate saturated solution (2×200 mL). The aqueous extract was acidified with 6N HCl and extracted with ethyl acetate (2×300 mL). The organic phase was washed with water (200 mL), dried over anhydrous magnesium sulfate and evaporated to dryness to give 13.9 g of [[[[(4-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as a solid, m.p. 110-113° C. Mass spectrum (El, M.+) m/z 288/290. 1H-NMR (DMSO-d6; 400 MHz) δ□13.20 (br s, 1H), 10.12 (s, 1H), 7.34-7.19 (m, 3H),4.69 (q, 2H), 3.55 (s, 3H), and 2.17 ppm (s, 3H). was heated at reflux for one hour evaporated to dryness The residue was dissolved in ethyl acetate (200 mL) extracted with sodium bicarbonate saturated solution (2×200 mL) The aqueous extract extracted with ethyl acetate (2×300 mL) The organic phase was washed with water (200 mL) dried over anhydrous magnesium sulfate evaporated to dryness

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

実験手順: The title compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113°-115° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (EI, M.+) m/z 254/256. The title compound was prepared by the procedure Crystallization from diethyl ether

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: (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Chloro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-Chloro-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-chloro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.

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

実験手順: (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Chloro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-Chloro-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-chloro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 202 mg (1.1 mmol) of 4-chloro-2-methyl-phenyl isothiocyanate (Maybridge) are added and the reaction mixture is stirred overnight at RT and finally for 16 hours at 60° C. Working-up analogously to Example 66 and stirring in DMSO/ethyl acetate yield 3-[(4-chloro-2-methyl-phenyl-amino)-thiocarbonyl-amino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100)=12.2; FAB-MS: (M+H)+=444.

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

実験手順: A mixture of ethyl N-propargylaminoacetate (10.0 g), 4-chloro-2-methylphenylisothiocyanate (12.9 g), triethylamine (7.1 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1 N HCl (100 mL), then with water. The organic layer was dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid was collected by filtration. Recrystallization from Hexane-EtOAc afford the title compound (5.2 g) as yellow solid, m.p. 99°-102° C. Anal. Calcd. for. C13H11N2O Cl S: C, 56.01; H, 3.98; N, 10.05. Found: C, 55.61; H, 3.83; N, 10.0. Mass spectrum (EI, M.+) m/z 278. was heated at reflux for 3 hours washed with 1 N HCl (100 mL) The organic layer was dried over anhydrous magnesium sulfate evaporated to dryness The residual oil was triturated with hexane The solid was collected by filtration Recrystallization from Hexane-EtOAc

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

実験手順: The title compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113°-115° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (El, M.+) m/z 254/256. The title compound was prepared by the procedure Crystallization from diethyl ether