1,3-diaminopropan-2-ol

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:0.00; pressure:0.00; stir:

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

Procedure: A solution of 1,5-di-(phenyl)-3-pentanone (9.5 g., 0.04 mole) in 50 cc. of anhydrous ethanol is added dropwise over about 20 minutes to a stirred solution of 1,3-diamino-2-hydroxypropane (25 g., 0.27 mole) in 200 cc. of ethanol. The resulting mixture is then heated at reflux for about two hours, allowed to cool, 1.0 g. platinum oxide added, and the mixture reduced under a 40 psi hydrogen atmosphere until hydrogen uptake ceases. The mixture is then filtered from the catalyst, concentrated in vacuo to remove the ethanol, the residue taken up in ether (250 cc.), washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to yield the product 1-amino-3-[1,5-di-(phenyl)-3-pentylamino]-2-propanol. The resulting mixture is then heated at reflux for about two hours to cool The mixture is then filtered from the catalyst concentrated in vacuo to remove the ethanol washed with water dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: Cbz-leucine (660 mg, 2.5 mmol), EDCI (480 mg, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DMF (10 ml) with 1,3-diamino-propan-2-ol (225 mg, 2.5 mmol) and was stirred at RT overnight. N-methyl morpholine (0.41 ml, 3.75 mmol) was added followed by 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride (820 mg, 2.5 mmol, Maybridge) was added and the reaction was stirred 3 h at RT. The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude 1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-ol was then dissolved in acetone (5.0 ml) and Jones reagent (3.0 ml, 1.5 M) was added dropwise, and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2×20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/methylene chloride), then the product was triturated from methylene chloride to give the title compound as a white solid (26 mg, 2%). MS(ES) M+H+=627. was added the reaction was stirred 3 h at RT The reaction was partitioned between water and EtOAc the combined organics were dried with magnesium sulfate concentrated in vacuo The crude 1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-ol was then dissolved in acetone (5.0 ml) Jones reagent (3.0 ml, 1.5 M) was added dropwise the reaction was stirred overnight at RT The excess Jones reagent was then quenched with isopropanol (1.0 ml) the reaction was diluted with EtOAc (20 ml) was extracted with water (2×20 ml) to remove the inorganic salts The combined organics were dried with magnesium sulfate filtered concentrated chromatographed (silica gel, 2-5% MeOH/methylene chloride) the product was triturated from methylene chloride

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

Procedure: To a solution of (R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxy pentyl)piperidine-1-carbonyl chloride (<0.05 mmol) in CH2Cl2, there was added excess 1,3-diaminopropan-2-ol (˜0.1 mL). The resulting solution was stirred at rt for 1 h, the CH2Cl2 was removed, and the residue was purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-amino-2-hydroxypropyl)piperidine-1-carboxamide (10.0 mg, 39%) as its TFA salt. 1H NMR (400 MHz, CD3OD): 7.64 (d, 1H), 7.32 (d, 1H), 7.04-7.20 (m, 4H), 6.74 (d, 1H), 6.56 (d, 1-H), 4.40 (d, 1H), 3.82 (m, 2H), 3.26 (t, 2H), 3.24 (s, 3H), 2.96 (m, 1H), 2.78 (m, 2H), 2.62 (q, 2H), 2.40 (m, 2H), 1.94 (m, 1H), 1.22-1.64 (m, 7H), 1.08 (t, 3H), 0.98 (m, 1H); MS m/z 514 (M+H+). the CH2Cl2 was removed the residue was purified by prep HPLC

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

Procedure: To a solution of (R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxy pentyl)piperidine-1-carbonyl chloride (<0.05 mmol) in CH2Cl2, there was added excess 1,3-diaminopropan-2-ol (˜0.1 mL). The resulting solution was stirred at rt for 1 h, the CH2Cl2 was removed, and the residue was purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-amino-2-hydroxypropyl)piperidine-1-carboxamide (10.0 mg, 39%) as its TFA salt. 1H NMR (400 MHz, CD3OD): 7.64 (d, 1H), 7.32 (d, 1H), 7.04-7.20 (m, 4H), 6.74 (d, 1H), 6.56 (d, 1-H), 4.40 (d, 1H), 3.82 (m, 2H), 3.26 (t, 2H), 3.24 (s, 3H), 2.96 (m, 1H), 2.78 (m, 2H), 2.62 (q, 2H), 2.40 (m, 2H), 1.94 (m, 1H), 1.22-1.64 (m, 7H), 1.08 (t, 3H), 0.98 (m, 1H); MS m/z 514 (M+H+). the CH2Cl2 was removed the residue was purified by prep HPLC

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

Procedure: Cbz-leucine (660 mg, 2.5 mmol), EDCI (480 mg, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DMF (10 ml) with 1,3-diamino-propan-2-ol (225 mg, 2.5 mmol) and was stirred at RT overnight N-methyl morpholine (0.41 ml, 3.75 mmol) was added followed by 4-(3-Chloro-2-cyano-phenoxy)phenyl sulfonyl chloride (820 mg, 2.5 mmol, Maybridge) was added and the reaction was stirred 3 h at RT. The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude 1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-ol was then dissolved in acetone (5.0 ml) and Jones reagent (3.0 ml, 1.5 M) was added dropwise, and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2×20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel 2-5% MeOH/methylene chloride), then the product was triturated from methylene chloride to give the title compound as a white solid (26 mg, 2%). MS(ES) M+H+ =627. was added was added The reaction was partitioned between water and EtOAc the combined organics were dried with magnesium sulfate concentrated in vacuo The crude 1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-ol was then dissolved in acetone (5.0 ml) Jones reagent (3.0 ml, 1.5 M) was added dropwise the reaction was stirred overnight at RT The excess Jones reagent was then quenched with isopropanol (1.0 ml) the reaction was diluted with EtOAc (20 ml) was extracted with water (2×20 ml) to remove the inorganic salts The combined organics were dried with magnesium sulfate filtered concentrated chromatographed (silica gel 2-5% MeOH/methylene chloride) the product was triturated from methylene chloride

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

Procedure: To a solution of acetic acid 1-acetoxymethyl-2-[3-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-5-isocyanato-benzoylamino]-ethyl ester in dichloromethane was added 1,3-diamino-2-hydroxypropane (0.5 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give Acetic acid 2-acetoxy-3-[3-[3-(3-{3-[3,5-bis-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo phenyl]-ureido}-2-hydroxy-propyl)-ureido]-5-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-benzoylamino]-propyl ester. This was dissolved in methanol and treated with aqueous ammonia. The material was purified by preparatie HPLC to give 1,3-bis-[N,N′-Bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-5-ureido-isophthalamide]-2-hydroxypropane as a white powder after freeze drying. purified by column chromatography