N'-hydroxyethanimidamide

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: Ethyl 2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added and treated with 80 mg potassium carbonate and 43 mg acetamide oxime at reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is chromatographed over silica to afford 0.221 g (94%) of the desired product as a yellow oil. heated to reflux at reflux filtered concentrated The residue is chromatographed over silica

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

Procedure: A 100 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 6 drops of DMF. Oxalyl chloride (0.248 ml, 2.85 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours then concentrated in vacuo to yield 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride as a brown solid. This material was suspended in chloroform (5 mL). N′-hydroxyacetamidine (0.186 g, 2.50 mmol), triethylamine (0.347 ml, 2.50 mmol), and chloroform (15 mL) were stirred together in a 50 mL flask to form a slurry, which was slowly added to the 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride suspension, then stirred for 1.5 hours at room temperature. The reaction mixture was diluted with chloroform (50 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was triturated with toluene, and the precipitate collected to obtain the title compound (0.282 g, 46% yield) as a tan solid. to form a slurry, which washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL) The organic layer was dried with MgSO4 filtered concentrated in vacuo The resulting brown solid was triturated with toluene the precipitate collected

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

Procedure: To a suspension of 1-(hydroxyimino)ethylamine (7.4 g) in dry tetrahydrofuran (450 ml) was added sodium hydride (3.7 g, 60% in mineral oil) carefully. The mixture was stirred at room temperature for 15 minutes, and refluxed for 30 minutes. To this mixture was added 3,5-bis(methoxycarbonyl)pyridine (15 g), and the mixture was refluxed for 3 hours. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (200 ml) under stirring. The aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylic acid (5.04 g). refluxed for 30 minutes the mixture was refluxed for 3 hours After being cooled to room temperature under stirring The resulting precipitate was collected by filtration washed with water dried in vacuo

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

Procedure: The title compound was prepared by a similar method to Preparation 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38], N′1-hydroxyethanimidamide [La Manna, et al, Theochem (1990), 69, 161-68], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford N′1-[((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)oxy]ethanimidamide as a colourless gum.

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

Procedure: 5-(5-Iodo-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 22) (200 mg, 0.42 mmol) and N′-hydroxyethanimidamide (EP 795 328) (95 mg, 1.28 mmol) were suspended in toluene (4 mL) and triethylamine (86 mg, 0.85 mmol) was added. Pd(PPh3)2Cl2 (15 mg, 0.02 mmol) was added and placed in a preheated oil bath at 95° C. under 1 atmosphere carbon monoxide. After 4 h a further portion of acetamidoxime (50 mg), triethylamine (43 mg) and Pd(PPh3)2Cl2 (15 mg) were added and stirring was continued at 95° C. for 14 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4), filtered and evaporated. Purification by flash column chromatography (gradient elution from dichloromethane:1% methanol:dichloromethane) gave 70 mg product. The cooled reaction mixture washed with water and brine dried (MgSO4) filtered evaporated Purification by flash column chromatography (gradient elution from dichloromethane:1% methanol:dichloromethane)

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

Procedure: Ethyl 2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added. and treated with 80 mg potassium carbonate and 43 mg acetamide oxime at reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is chromatographed over silica to afford 0.221 g (94%) of the desired product as a yellow oil. heated to reflux at reflux filtered concentrated The residue is chromatographed over silica

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

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