Sodium cyanoborohydride

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

Procedure: To a homogeneous solution of 8.42 parts of (S)-2-aminopropanamide monohydrobromide, 12.26 parts of sodium acetate and 79 parts of methanol there were added 10.96 parts of 2,6-dichloro-3-nitrobenzaldehyde and, after 1/2 hour, a mixture of 3.77 parts of sodium cyanotrihydroborate and 7.9 parts of methanol. The whole was stirred for 45 min at room temperature. After acidifying to pH 1 with HCl (3N), stirring was continued overnight. The reaction mixture was evaporated and the residue was basified with NaHCO3 (sat.). The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was recrystallized from 2-propanol, yielding 10.29 parts (70.7%) of (S)-2-[[(2,6-dichloro-3-nitrophenyl)methyl]amino]propanamide (interm. 69). stirring was continued overnight The reaction mixture was evaporated The product was extracted with dichloromethane the extract was dried filtered evaporated The residue was recrystallized from 2-propanol

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

Procedure: A flask, under nitrogen, was charged with a mixture of 12.4 grams (0.05 mole) of 1-phenyl-2,2,6,6-tetra methyl-4-phosphorinanone, 17.7 grams (0.30 mole) of n-propylamine, 1.89 grams (0.03 mole) of sodium cyanotrihydroborate, 20 mls of 5N methanolic hydrochloric acid and 150 mls of methanol. The mixture was stirred at ambient temperature for three days and then treated with 20 mls of conc. hydrochloric acid. The reaction mixture was concentrated in vacuo and 30 mls of water and 25 mls of diethylether were added. The layers were separated and to the aqueous layer was added 8 grams of solid sodium hydroxide. The resultant basic mixture was extracted sequentially with five 25 ml portions of diethylether. The combined extracts were dried over anhydrous sodium sulfate, the solvent removed in vacuo and the residue distilled under reduced pressure to give 11.2 grams (77% yield) of colorless liquid, b.p. 140°-144° C. (0.1 mm Hg) The reaction mixture was concentrated in vacuo and 30 mls of water and 25 mls of diethylether were added The layers were separated and to the aqueous layer was added 8 grams of solid sodium hydroxide The resultant basic mixture was extracted sequentially with five 25 ml portions of diethylether The combined extracts were dried over anhydrous sodium sulfate the solvent removed in vacuo the residue distilled under reduced pressure

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

Procedure: To a stirred mixture of 58.9 parts of potassium acetate, 100.5 parts of ethyl glycine monohydrochloride and 790 parts of ethanol, there were added 100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (prepared following the procedure described in Example 9 or Example 14. After stirring for 1/2 hour, there were added portionwise 9.4 parts of sodium cyanotrihydroborate. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1). The eluent of the desired fraction was evaporated, yielding 71 parts (56.2%) of ethyl N-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66). prepared Stirring was continued for 1/2 hour at room temperature The reaction mixture was evaporated the residue was partitioned between water and dichloromethane The organic layer was separated washed with water dried filtered evaporated The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1) The eluent of the desired fraction was evaporated

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

Procedure: To a solution of (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-amino-3-methylcyclohexyl)carbamate (1.0 equiv.) in MeOH (0.10 M) was added benzaldehyde (1.3 equiv.). After 3 hrs, sodium cyanotrihydroborate (2.5 equiv.) was added and the mixture was stirred at rt for 16 hrs. The reaction mixture was quenched by the addition of water, and volatiles were removed in vacuo. The mixture was extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (0.10 M) and paraformaldehyde (5.0 equiv.) was added. After 16 hrs, sodium cyanotrihydroborate (5.0 equiv.) was added and the mixture was left stirred at rt for 16 hrs. The reaction was quenched by the addition of water, and volatiles were removed in vacuo. The mixture was extracted with DCM. The combined organic phases were dried with sodium sulfate, filtered, concentrated and purified by ISCO Chromatography. The product was dissolved in MeOH (0.10 M) and treated with Pd(OH)2 (0.50 equiv.) under H2 for 5 hrs at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated to yield (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-3-methyl-2-(methylamino)cyclohexyl)carbamate in 75% yield. LC/MS (m/z)=435.2 (MH+), Rt=0.64 min. The reaction mixture was quenched by the addition of water, and volatiles were removed in vacuo The mixture was extracted with ethyl acetate The combined organic phases were dried with sodium sulfate filtered concentrated The residue was dissolved in MeOH (0.10 M) After 16 hrs the mixture was left stirred at rt for 16 hrs The reaction was quenched by the addition of water, and volatiles were removed in vacuo The mixture was extracted with DCM The combined organic phases were dried with sodium sulfate filtered concentrated purified by ISCO Chromatography The product was dissolved in MeOH (0.10 M) The reaction was filtered through a pad of celite the cake was washed with MeOH The organics were concentrated

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

Procedure: To a solution of (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-amino-3-methylcyclohexyl)carbamate (1.0 equiv.) in MeOH (0.10 M) was added benzaldehyde (1.3 equiv.). After 3 hrs, sodium cyanotrihydroborate (2.5 equiv.) was added and the mixture was stirred at rt for 16 hrs. The reaction mixture was quenched by the addition of water, and volatiles were removed in vacuo. The mixture was extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (0.10 M) and paraformaldehyde (5.0 equiv.) was added. After 16 hrs, sodium cyanotrihydroborate (5.0 equiv.) was added and the mixture was left stirred at rt for 16 hrs. The reaction was quenched by the addition of water, and volatiles were removed in vacuo. The mixture was extracted with DCM. The combined organic phases were dried with sodium sulfate, filtered, concentrated and purified by ISCO Chromatography. The product was dissolved in MeOH (0.10 M) and treated with Pd(OH)2 (0.50 equiv.) under H2 for 5 hrs at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated to yield (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-3-methyl-2-(methylamino)cyclohexyl)carbamate in 75% yield. LC/MS (m/z)=435.2 (MH+), Rt=0.64 min. The reaction mixture was quenched by the addition of water, and volatiles were removed in vacuo The mixture was extracted with ethyl acetate The combined organic phases were dried with sodium sulfate filtered concentrated The residue was dissolved in MeOH (0.10 M) After 16 hrs the mixture was left stirred at rt for 16 hrs The reaction was quenched by the addition of water, and volatiles were removed in vacuo The mixture was extracted with DCM The combined organic phases were dried with sodium sulfate filtered concentrated purified by ISCO Chromatography The product was dissolved in MeOH (0.10 M) The reaction was filtered through a pad of celite the cake was washed with MeOH The organics were concentrated

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

Procedure: Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidine]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (10 ml) was added followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the solution, methylene chloride (1 ml) and triethylamine (1 ml) were added followed by stirring at room temperature for 5 minutes. The solution was concentrated under reduced pressure and the residue was dissolved in methanol (10 ml). To the solution, 4-trifluoromethylbenzaldehyde (0.23 ml, 1.67 mmol), sodium cyanotrihydroborate (105 mg, 1.67 mmol) and acetic acid (0.1 ml) were added with cooling on ice-bath followed by stirring at room temperature overnight. To the solution, a saturated aqueous sodium hydrogencarbonate solution and methylene chloride were added followed by stirring. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) and crystallized from methylene chloride-diisopropyl ether to afford 1-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin])-1′-yl)-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]ethanone (226 mg, yield 67%) as a white powder. The reaction mixture was concentrated under reduced pressure To the solution, methylene chloride (1 ml) and triethylamine (1 ml) were added by stirring at room temperature for 5 minutes The solution was concentrated under reduced pressure the residue was dissolved in methanol (10 ml) with cooling on ice-bath by stirring at room temperature overnight by stirring The organic phase was dried over magnesium sulfate filtered The resulting filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) crystallized from methylene chloride-diisopropyl ether

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

Procedure: A mixture of tert-butyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-homopiperazin-1-carboxylate prepared in Example 645 (346 mg, 0.91 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (0.27 ml, 1.96 mmol) was added. The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (496 mg, 2.72 mmol), sodium cyanotrihydroborate (171 mg, 2.72 mmol) and acetic acid (0.17 ml, 2.72 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was poured into a saturated sodium hydrogencarbonate solution, then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1) to afford 2-[4-(biphenyl-4-ylmethyl)homopiperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (251 mg, yield 62%) as a white powder. The reaction mixture was concentrated under reduced pressure the residue was dissolved in methylene chloride (10 ml) The solution was concentrated under reduced pressure the residue was dissolved in methanol (10 ml) by stirring at room temperature overnight extracted with methylene chloride The organic phase was dried over magnesium sulfate filtered The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1)

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

Procedure: A mixture of tert-butyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-homopiperazin-1-carboxylate prepared in Example 645 (346 mg, 0.91 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (0.27 ml, 1.96 mmol) was added. The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (496 mg, 2.72 mmol), sodium cyanotrihydroborate (171 mg, 2.72 mmol) and acetic acid (0.17 ml, 2.72 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was poured into a saturated sodium hydrogencarbonate solution, then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1) to afford 2-[4-(biphenyl-4-ylmethyl)homopiperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (251 mg, yield 62%) as a white powder. The reaction mixture was concentrated under reduced pressure the residue was dissolved in methylene chloride (10 ml) The solution was concentrated under reduced pressure the residue was dissolved in methanol (10 ml) by stirring at room temperature overnight extracted with methylene chloride The organic phase was dried over magnesium sulfate filtered The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1)

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

Procedure: A mixture of tert-butyl (R)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 396 (100 mg, 0.27 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (1 ml, 7.17 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (149 mg, 0.82 mmol), sodium cyanotrihydroborate (51 mg, 0.82 mmol) and acetic acid (48 μl, 0.82 mmol) were added in this order followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added a saturated sodium hydrogencarbonate solution. The precipitates were filtered off and purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (67 mg, yield 57%) as a light yellow powder. The reaction mixture was concentrated under reduced pressure The residue was dissolved in methylene chloride (5 ml) the solution was concentrated under reduced pressure The residue was dissolved in methanol (5 ml) by stirring at room temperature for 15 hours The reaction mixture was concentrated under reduced pressure the residue was added a saturated sodium hydrogencarbonate solution The precipitates were filtered off purified by silica gel column chromatography (ethyl acetate)

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

Procedure: A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (1.7 g, 4.6 mmol), trifluoroacetic acid (10 ml) and methylene chloride (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml). To the solution, 4′-trifluoromethylbiphenyl-4-carboaldehyde (2.3 g, 9.19 mmol), sodium cyanotrihydroborate (580 mg, 9.23 mmol) and acetic acid (0.55 ml, 9.62 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-methyl-6-nitro-2-[4-(4′-trifluoromethylbiphenyl-4-ylmethyl)piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (1.47 g, yield 63%) as a white powder. The reaction mixture was concentrated under reduced pressure The residue was dissolved in methanol (30 ml) by stirring at room temperature overnight The reaction mixture was concentrated under reduced pressure To the residue, a saturated sodium hydrogencarbonate solution was added the solution was extracted with methylene chloride twice washed with a saturated sodium hydrogencarbonate solution a saturated saline solution in this order, dried over magnesium sulfate filtered The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1)

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

Procedure: A mixture of tert-butyl (R)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 395 (101.5 mg, 0.29 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (2 ml, 14.35 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (156 mg, 0.86 mmol), sodium cyanotrihydroborate (53 mg, 0.84 mmol) and acetic acid (0.05 ml, 0.87 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-[4-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (56 mg, yield 46%) as a white powder. The reaction mixture was concentrated under reduced pressure The residue was dissolved in methylene chloride (5 ml) the solution was concentrated under reduced pressure The residue was dissolved in methanol (5 ml) by stirring at room temperature overnight The reaction mixture was concentrated under reduced pressure To the residue, a saturated sodium hydrogencarbonate solution was added the solution was extracted with methylene chloride twice washed with a saturated sodium hydrogencarbonate solution a saturated saline solution in this order, dried over magnesium sulfate filtered The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate)

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

Procedure: A mixture of tert-butyl (R)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 395 (101.5 mg, 0.29 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (2 ml, 14.35 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (156 mg, 0.86 mmol), sodium cyanotrihydroborate (53 mg, 0.84 mmol) and acetic acid (0.05 ml, 0.87 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-[4-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (56 mg, yield 46%) as a white powder. The reaction mixture was concentrated under reduced pressure The residue was dissolved in methylene chloride (5 ml) the solution was concentrated under reduced pressure The residue was dissolved in methanol (5 ml) by stirring at room temperature overnight The reaction mixture was concentrated under reduced pressure To the residue, a saturated sodium hydrogencarbonate solution was added the solution was extracted with methylene chloride twice washed with a saturated sodium hydrogencarbonate solution a saturated saline solution in this order, dried over magnesium sulfate filtered The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate)