2-(methylamino)acetonitrile

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 solution of 3.22 grams (0.0225 mol) of 1,3-dimethyl-4-amino-4-imidazoline-2-thione (prepared from methylaminoacetonitrile and methyl isothiocyanate by the method of T. Kinoshita et al, Bull. Chem. Soc. Japan., 53, 442 (1980)) in 12 mL of pyridine under an atmosphere of nitrogen was added with stirring 2.61 grams (0.0457 mol) of methyl isocyanate. The mixture became exothermic. Stirring was continued overnight whereupon a solid precipitate formed in the reaction mixture. The latter was collected by filtration and washed with isopropyl alcohol to obtain 2.11 grams of 1,3-dimethyl-4-(methylaminocarbonylamino)-imidazoline-2-thione, m.p. 200°-201° C. formed in the reaction mixture The latter was collected by filtration washed with isopropyl alcohol

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

Procedure: To a solution of 3.22 grams (0.0225 mol) of 1,3-dimethyl-4-amino-4-imidazoline-2-thione (prepared from methylaminoacetonitrile and methyl isothiocyanate by the method of T. Kinoshita et al, Bull. Chem. Soc. Japan., 53, 442 (1980)) in 12 mL of pyridine under an atmosphere of nitrogen was added with stirring 2.61 grams (0.0457 mol) of methyl isocyanate. The mixture became exothermic. Stirring was continued overnight whereupon a solid precipitate formed in the reaction mixture. The latter was collected by filtration and washed with isopropyl alcohol to obtain 2.11 grams of 1,3-dimethyl-4-(methylaminocarbonylamino)-imidazoline-2-thione, m.p. 200°-201° C. formed in the reaction mixture The latter was collected by filtration washed with isopropyl alcohol

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

Procedure: A mixture of hydroxy-{3-[1-hydroxymethyl-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (0.1 g, 0.25 mmol), methylaminoacetonitrile (20 μl, 0.27 mmol), diisopropylethylamine (DIEA, 87 μl, 0.48 mmol), N,N,N′,N′,-Tetramethyl-O-(7-azabenotriazol-1-yl)uronium hexafluorophosphate (HATU, 101 mg, 0.27 mmol) in DMF (3 ml) was stirred at room temperature overnight. The reaction mixture was dissolved in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica gel chromatography. The resulting material was dissolved in 3 ml of methanol, aqueous NaOH was added (1 ml, 2 N in H2O) and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude was neutralized with 500 μl of 1N HCl and purified by mass-triggered reverse phase HPLC to afford N-cyanomethyl-2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl]-phenyl}-N-methyl-acetamide as a yellow powder (56 mg, 53% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.02 (s, 3H), 3.87 (s, 3H), 4.14 (s, 2H), 5.55 (s, 1H), 7.10 (m, 1H), 7.23 (d, 1H), 7.40 (d, 1H), 7.45-7.52 (m, 2H), 7.66 (d, 1H), 7.72 (m, 2H), 8.32 (s, 1H), 8.33 (s, 1H). MS: m/z 427.5 (M+H+). subsequently extracted with 1N HCl, saturated NaHCO3, brine dried with Na2SO4 concentrated to dryness The crude was purified by silica gel chromatography The resulting material was dissolved in 3 ml of methanol aqueous NaOH was added (1 ml, 2 N in H2O) the mixture stirred overnight at room temperature The solvent was removed under reduced pressure purified by mass-triggered reverse phase HPLC

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

Procedure: To a solution of 2-hydroxy-4-methoxybenzoyl chloride (22.19 g, 118.9 mmol) in 500 CH2Cl2 were added (methylamino)acetonitrile (10 g, 142.7 mmol) and 2,6-lutidine (19.1 g, 178.4 mmol). The reaction was stirred at rt overnight. The reaction mixture was then partitioned between EtOAc and 1(N) aq HCl. Organic layer washed with 1(N) aq HCl (2×), dried over Na2SO4 and concentrated to light yellow viscous material (24.63 g, 94%). This material was used in the next step without further purification. The reaction mixture was then partitioned between EtOAc and 1(N) aq HCl Organic layer washed with 1(N) aq HCl (2×) dried over Na2SO4 concentrated to light yellow viscous material (24.63 g, 94%) This material was used in the next step without further purification

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

Procedure: A solution of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid (0.060 g, 0.18 mmol), methylaminoacetonitrile (0.200 mL, 1.64 mmol) and EDCI (0.315 g, 1.64 mmol) in 3 mL of ethanol and 3 mL of dichloromethane was stirred for 1 h, then concentrated. The resulting residue was partitioned between 30 ml of ethyl acetate and 30 mL of a 10% citric acid solution, and the aqueous layer was extracted 30 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->40% EtOAc/hexanes) afforded 0.040 g (58%) of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid cyanomethyl-methyl-amide as a pale yellow solid. concentrated The resulting residue was partitioned between 30 ml of ethyl acetate and 30 mL of a 10% citric acid solution the aqueous layer was extracted 30 mL of ethyl acetate The combined organic layers were dried over MgSO4 filtered concentrated to a residue

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

Procedure: A solution of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid (0.060 g, 0.18 mmol), methylaminoacetonitrile (0.200 mL, 1.64 mmol) and EDCI (0.315 g, 1.64 mmol) in 3 mL of ethanol and 3 mL of dichloromethane was stirred for 1 h, then concentrated. The resulting residue was partitioned between 30 ml of ethyl acetate and 30 mL of a 10% citric acid solution, and the aqueous layer was extracted 30 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->40% EtOAc/hexanes) afforded 0.040 g (58%) of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid cyanomethyl-methyl-amide as a pale yellow solid. concentrated The resulting residue was partitioned between 30 ml of ethyl acetate and 30 mL of a 10% citric acid solution the aqueous layer was extracted 30 mL of ethyl acetate The combined organic layers were dried over MgSO4 filtered concentrated to a residue

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In this example 21 ml (0.15 mole) of triethylamine was added over a 5 minute period to a cooled solution containing 16 g (0.15 mole) of the hydrochloride salt of methylaminoacetonitrile in 150 ml of methylene chloride. The mixture was stirred at 20° C. for 15 minutes and then 7.9 g (0.1 mole) of pyridine was added. Then 25.9 g (0.1 mole) of 3-trifluoromethylbenzylsulfonylchloride dissolved in about 50 ml methylene chloride was added to the reaction mixture. The reaction mixture was maintained at 20° C. during the addition and then refluxed for three hours. The mixture was cooled to room temperature and washed once with 200 ml of water and then washed twice with 100 ml of aqueous 5 wt. % hydrochloric acid. The washed mixture was dried over magnesium sulfate and evaporated under vacuum affording 28.2 g of the title compound as a solid residue. was added over a 5 minute period to a cooled solution was added to the reaction mixture The reaction mixture was maintained at 20° C. during the addition refluxed for three hours The mixture was cooled to room temperature washed once with 200 ml of water washed twice with 100 ml of aqueous 5 wt. % hydrochloric acid The washed mixture was dried over magnesium sulfate evaporated under vacuum

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

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

Procedure: The experimental protocol used is identical to that described for the compound of Example 26, methylaminoacetonitrile being used as starting product in place of the N-methylpropargylamine. A white solid is obtained with a yield of 36%. Melting point: 165-167.8° C. A white solid is obtained with a yield of 36%