methoxymethanamine

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

Procedure: N-Methoxymethylamine (1.05 g) was dissolved in THF-water (25:1, 5 ml) with anhydrous K2CO3 (1.5 g), and the solution was stirred at room temperature for 30 minutes. It was then transferred by syringe into a flask containing 3-[(3-chlorophenyl)thiomethyl]-2-pyridinecarboxylic acid (2.0 g, 7.16 mmol) in a mixture of THF (3 ml), DMF (2 ml) and NMM (0.5 ml). HOBT (180 mg, 1.33 mmol) and EDCI (255 mg, 1.33 mmol) were added at 0° C. and the mixture was then stirred 28 hours at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The product was chromatographed on silica in 2%MeOH/CH2Cl2 and afforded 200 mg of 3-[(3-chlorophenyl)thiomethyl)]-N-methoxy-N-methyl-2-pyridinecarboxamide; MS (EI, M)=292; MS (CI, M+H)=293. It was then transferred by syringe into a flask the mixture was then stirred 28 hours at room temperature extracted with EtOAc The extracts were washed with brine dried (Na2SO4) filtered concentrated The product was chromatographed on silica in 2%MeOH/CH2Cl2

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

Procedure: A stirred solution of N-methoxymethylamine (3.47 g) and triethylamine (10.4 mL) in dichloromethane (100 mL) at 5° C. is treated dropwise with 3-iodobenzoyl chloride (9.8 g). The reaction mixture is stirred at room temperature for 2 hours, washed twice with water (70 mL), dried over magnesium sulphate, and evaporated to give N-methoxy-N-methyl-3-iodobenzamide (9.8 g) as a brown oil. washed twice with water (70 mL) dried over magnesium sulphate evaporated

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

Procedure: Weinreb amide formation. 4-carboxy isoxazole (obtained from Steps 1-4 above) was dissolved in THF and activated with EDC:HOBt:DIEA (1.5:1.5:1.5) and allowed to stand at rt for 5min. N-methoxymethylamine (1.5 equiv.) was then added. The reaction mixture was allowed to stand at rt overnight, after which it was diluted with EtOAc and washed with 10% citric acid, 10% NaHCO3, and brine. The solvent was removed, and the residue was purified by flash chromatography (EtOAc/petrol) and lyophilized in 90% MeCN/H2O to give the desired product as a white powder. to stand at rt overnight washed with 10% citric acid, 10% NaHCO3, and brine The solvent was removed the residue was purified by flash chromatography (EtOAc/petrol)

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

Procedure: To a stirred solution of isonicotinic acid (20.0 g, 162 mmol) in DCM (400 mL) were added HATU (92.6 g, 243 mmol), N-methoxy methylamine (17.24 g, 178 mmol) and TEA (68.7 mL, 487 mmol) at RT under nitrogen atmosphere. The reaction mixture was then stirred at RT for 12 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (3×500 mL). The combined organic extracts were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 30-40% EtOAc in Hexane to afford to afford N-methoxy-N-methylisonicotinamide (15.0 g, 55%) as an oil. the aqueous layer was extracted with DCM (3×500 mL) The combined organic extracts were washed with water (150 mL), brine (150 mL) dried over anhydrous Na2SO4 filtered concentrated in vacuo to obtain the crude product The crude material was purified via silica gel column chromatography eluting with 30-40% EtOAc in Hexane to afford

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

Procedure: N-Methoxymethylamine (1.05 g) was dissolved in THF-water (25:1, 5 ml) with anhydrous K2CO3 (1.5 g), and the solution was stirred at room temperature for 30 minutes. It was then transferred by syringe into a flask containing 3-[(3-chlorophenyl)thiomethyl]-2-pyridinecarboxylic acid (2.0 g, 7.16 mmol) in a mixture of THF (3 ml), DMF (2 ml) and NMM (0.5 ml). HOBT (180 mg, 1.33 mmol) and EDCI (255 mg, 1.33 mmol) were added at 0° C. and the mixture was then stirred 28 hours at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The product was chromatographed on silica in 2%MeOH/CH2Cl2 and afforded 200 mg of 3-[(3-chlorophenyl)thiomethyl)]-N-methoxy-N-methyl-2-pyridinecarboxamide; MS (EI, M)=292; MS (CI, M+H)=293. It was then transferred by syringe into a flask the mixture was then stirred 28 hours at room temperature extracted with EtOAc The extracts were washed with brine dried (Na2SO4) filtered concentrated The product was chromatographed on silica in 2%MeOH/CH2Cl2

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

Procedure: A stirred solution of N-methoxymethylamine (3.47 g) and triethylamine (10.4 mL) in dichloromethane (100 mL) at 5° C. is treated dropwise with 3-iodobenzoyl chloride (9.8 g). The reaction mixture is stirred at room temperature for 2 hours, washed twice with water (70 mL), dried over magnesium sulphate, and evaporated to give N-methoxy-N-methyl-3-iodobenzamide (9.8 g) as a brown oil. washed twice with water (70 mL) dried over magnesium sulphate evaporated

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

Procedure: A stirred solution of N-methoxymethylamine (3.47 g) and triethylamine (10.4 mL) in dichloromethane (100 mL) at 5° C. is treated dropwise with 3-iodobenzoyl chloride (9.8 g). The reaction mixture is stirred at room temperature for 2 hours, washed twice with water (70 mL), dried over magnesium sulphate, and evaporated to give N-methoxy-N-methyl-3-iodobenzamide (9.8 g) as a brown oil. washed twice with water (70 mL) dried over magnesium sulphate evaporated

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

Procedure: 3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 27d (1.84 g, 5.5 mmol) and N-methoxy methyl-amine (0.805 g, 8.25 mmol) were dissolved in 50 mL of dichloromethane under stirring, and triethylamine (3 mL, 22 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.1 g, 8.25 mmol) were then added to the solution. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (2.1 g) as a white solid. The reaction mixture was reacted overnight at room temperature The reaction mixture was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: 250 mg (0.59 mmol) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyric acid in 7 ml CH2Cl2 were treated with 0.33 ml (2.95 mmol) NMM, 18 mg (0.12 mmol, 0.2 eq) HOBT, 147 mg (0.77 mmol, 1.3 eq) EDCI.hydrochloride and 127 mg (1.3 mmol, 2.2 eq) N-Methoxymethylamine.hydro-chloride. The mixture was stirred at RT for 3 h, was acidified by adding 1M KHSO4 and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 260 mg (94%) trans-N-Methoxy-N-methyl-4-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyramide as light yellow oil, MS: 467 (MH+). extracted with CH2Cl2 The combined organic phases were washed with brine dried over Na2SO4 evaporated

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

Procedure: 3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 27d (1.84 g, 5.5 mmol) and N-methoxy methyl-amine (0.805 g, 8.25 mmol) were dissolved in 50 mL of dichloromethane under stirring, and triethylamine (3 mL, 22 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.1 g, 8.25 mmol) were then added to the solution. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (2.1 g) as a white solid. The reaction mixture was reacted overnight at room temperature The reaction mixture was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: 250 mg (0.59 mmol) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyric acid in 7 ml CH2Cl2 were treated with 0.33 ml (2.95 mmol) NMM, 18 mg (0.12 mmol, 0.2 eq) HOBT, 147 mg (0.77 mmol, 1.3 eq) EDCI.hydrochloride and 127 mg (1.3 mmol, 2.2 eq) N-Methoxymethylamine.hydro-chloride. The mixture was stirred at RT for 3 h, was acidified by adding 1M KHSO4 and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 260 mg (94%) trans-N-Methoxy-N-methyl-4-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyramide as light yellow oil, MS: 467 (MH+). extracted with CH2Cl2 The combined organic phases were washed with brine dried over Na2SO4 evaporated

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

Procedure: 250 mg (0.59 mmol) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyric acid in 7 ml CH2Cl2 were treated with 0.33 ml (2.95 mmol) NMM, 18 mg (0.12 mmol, 0.2 eq) HOBT, 147 mg (0.77 mmol, 1.3 eq) EDCI.hydrochloride and 127 mg (1.3 mmol, 2.2 eq) N-Methoxymethylamine.hydro-chloride. The mixture was stirred at RT for 3 h, was acidified by adding 1M KHSO4 and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 260 mg (94%) trans-N-Methoxy-N-methyl-4-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyramide as light yellow oil, MS: 467 (MH+). extracted with CH2Cl2 The combined organic phases were washed with brine dried over Na2SO4 evaporated