morpholine-4-carbonitrile

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:

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (200 mg) produced in Example 1, step C, morpholine-4-carbonitrile (0.17 mL) and 4M hydrochloric acid/cyclopentylmethylether solution (3.0 mL) was stirred at 110° C. for 4 hr. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1) to give the title compound (144 mg) as a pale-yellow solid. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue The precipitate was collected by filtration washed with water The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (200 mg) produced in Example 1, step C, morpholine-4-carbonitrile (0.17 mL) and 4M hydrochloric acid/cyclopentylmethylether solution (3.0 mL) was stirred at 110° C. for 4 hr. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1) to give the title compound (144 mg) as a pale-yellow solid. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue The precipitate was collected by filtration washed with water The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of hydroxylamine (4.0 mL, 65 mmol) and morpholine-4-carbonitrile (5.00 g, 44.6 mmol) was heated at 80° C. for 24 h. After cooling to room temperature, the reaction mixture was diluted with MeOH and Et2O, then allowed to stand at room temperature for 2 days. The resultant precipitate was collected by filtration to give 9.02 g of the desired product as a white solid. After cooling to room temperature The resultant precipitate was collected by filtration

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (200 mg) produced in Example 1, step C, morpholine-4-carbonitrile (0.17 mL) and 4M hydrochloric acid/cyclopentylmethylether solution (3.0 mL) was stirred at 110° C. for 4 hr. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1) to give the title compound (144 mg) as a pale-yellow solid. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue The precipitate was collected by filtration washed with water The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1)

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

Procedure: In the manner given in Example 2, 4-morpholinecarbonitrile is treated with sodium methoxide in methanol to give methyl 4-morpholinecarboximidate.

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

Procedure: A solution of 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 26a (0.4 g, 1.28 mmol) in tetrahydrofuran (10 mL) under argon, was cooled to −78° C. A solution of 2.5 M n-butyllithium in hexanes (0.61 mL, 1.53 mmol) was added dropwise over 5 min. After the addition, stirring was continued for 15 min at −78° C. 4-Morpholinecarbonitrile (0.172 g, 1.53 mmol) was added all at once and reaction continued for 90 min at that temperature. A saturated ammonium chloride solution was added at −78° C. After warming to room temperature the mixture was made basic (pH 9) with concentrated ammonium hydroxide and the product was extracted with dichloromethane. The combined organics were dried with magnesium sulfate, the solvent was evaporated and the residue purified by flash chromatography eluting with 6% methanol in dichloromethane containing 0.6% of ammonium hydroxide, to yield 0.24 g of 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 27a. After the addition reaction continued for 90 min at that temperature the product was extracted with dichloromethane The combined organics were dried with magnesium sulfate the solvent was evaporated the residue purified by flash chromatography eluting with 6% methanol in dichloromethane containing 0.6% of ammonium hydroxide

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