1-isocyanatodecane

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

Procedure: Using the method of Example 2 above, but using ethyl 4-bromobutyrate, t-butyl N-[3-(ethoxycarbonyl)propyl]-N-benzyloxy carbamate was obtained as a colorless oil. This carbamate (6.17 g, 18.8 mmol) was dissolved in 3.3M HCl in ethyl acetate (50 ml) at room temperature under nitrogen. After one hour, the turbid solution was evaporated, and the residue was triturated with hexane. Filtration gave ethyl 4-(benzyloxyamino)butyrate hydrochloride as a white solid (4.59 g, 93% yield). To a solution of decyl isocyanate (0.92 g) in toluene (50 ml) was added this hydrochloride (1.40 g) in DMF (5 ml). Triethylamine (0.75 ml) was added, and the solution was stirred for one hour. The mixture was washed with 10% aqueous citric acid, and the organic solution was dried (MgSO4), filtered and evaporated. Purification by chromatography on silica gave N'-decyl-N-benzyloxy-N-[3-(ethoxycarbonylpropyl]urea as a colorless oil (1.58 g, 58% yield). The mixture was washed with 10% aqueous citric acid the organic solution was dried (MgSO4) filtered evaporated Purification by chromatography on silica

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

Procedure: To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C. The solution was refluxed for 20 minutes evaporated the residue triturated with pentane

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

Procedure: To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C. The solution was refluxed for 20 minutes evaporated the residue triturated with pentane

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-dihydroxypropylthio) propanoate (13) was stirred in anhydrous benzene (0.1 M) under nitrogen at room temperature. Decyl isocyanate (2.02 eq) and DMAP (dimethylaminopyridine, 2.02 eq) were added and the resulting mixture heated to 40° C. and stirred overnight. The reaction mixture was concentrated to remove benzene then reconstituted in DCM and purified on a COMBIFLASH® system (ISCO) using a gradient of 0-50% EtOAc/Hex to give the title product as a colorless oil. The reaction mixture was concentrated to remove benzene purified on a COMBIFLASH® system (ISCO)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-dihydroxypropylthio) propanoate (13) was stirred in anhydrous benzene (0.1 M) under nitrogen at room temperature. Decyl isocyanate (2.02 eq) and DMAP (dimethylaminopyridine, 2.02 eq) were added and the resulting mixture heated to 40° C. and stirred overnight. The reaction mixture was concentrated to remove benzene then reconstituted in DCM and purified on a COMBIFLASH® system (ISCO) using a gradient of 0-50% EtOAc/Hex to give the title product as a colorless oil. The reaction mixture was concentrated to remove benzene purified on a COMBIFLASH® system (ISCO)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-dihydroxypropylthio)propanoate (13) was stirred in anhydrous benzene (0.1 M) under nitrogen at room temperature. Decyl isocyanate (2.02 eq) and DMAP (dimethylaminopyridine, 2.02 eq) were added and the resulting mixture heated to 40° C. and stirred overnight. The reaction mixture was concentrated to remove benzene then reconstituted in DCM and purified on a COMBIFLASH® system (ISCO) using a gradient of 0-50% EtOAc/Hex to give the title product as a colorless oil. The reaction mixture was concentrated to remove benzene purified on a COMBIFLASH® system (ISCO)

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

Procedure: (5.1) To a stirring solution of 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester 4-tert-butyl ester (348 mg, 0.94 mmol) and DBU (0.35 mL, 360 mg, 2.4 mmol) in CH2Cl2 (10 mL) was added octyl isocyanate (0.166 mL, 146 mg, 0.94 mmol). The reaction was stirred RT for 16 h, and then solvent was removed under reduced pressure. The product was purified by column chromatography (5:1; hexanes:EtOAc) to give 431 mg of a solid (87%): Mp 92.0-94.0° C.; 1H NMR (CDCl3) δ 12.30 (s, 1H), 8.64 (s, 1H), 5.30 (t, 1H, J=6.0 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.29 (q, 2H, J=6.0 Hz), 2.74 (s, 3H), 1.90-1.50 (m, 4H), 1.61 (s, 9H), 1.28 (bs, 20H), 0.88 (m, 6H). MS (EI): 525.1 (m+). 3-Methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester. (5.2) The same method as for the preparation of 3-methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with octyl isocyanate (3.83 mL, 3.37 g, 21.7 mmol) afforded 3.42 g of a solid (38%) after column chromatography (9:1; hexanes:EtOAc): Mp 119.0-120.0° C.; 1H NMR (CDCl3) δ 11.03 (s, 1H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.03 (vt, 1H), 3.29 (q, 2H, J=6.6 Hz), 2.71 (s, 3H), 1.63-1.40 (m, 2H), 1.57 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J=6.6 Hz). MS (EI): 502.8 (m+). 3-Methyl-5-(3-tetradecyl-ureido)-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester. (5.3) The same method as for the preparation of 3-methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with tetradecyl isocyanate (0.33 mL, 287 mg, 1.2 mmol) afforded 253 mg of a solid (36%) after column chromatography (9:1; hexanes:EtOAc): Mp 104.5-106.0° C.; 1H NMR (CDCl3) δ 11.04 (s, 1H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.14 (t, 1H, J=6.2 Hz), 3.29 (q, 2H, J=6.2 Hz), 2.71 (s, 3H), 1.65-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 22H), 0.88 (t, 3H, J=6.0 Hz). MS (EI): 587.1 (m+). 5-(3-Hexadecyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester. (5.4) The same method as for the preparation of 3-methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with hexadecyl isocyanate (0.37 mL, 321 mg, 1.2 mmol) afforded 218 mg of a solid (30%) after column chromatography (9:1; hexanes:EtOAc): Mp 104.0-105.0° C.; 1H NMR (CDCl3) δ 11.04 (s, 1H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.14 (t, 1H, J=6.2 Hz), 3.29 (q, 2H, J=6.2 Hz), 2.71 (s, 3H), 1.65-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 26H), 0.88 (t, 3H, J=6.0 Hz). MS (EI): 615.1 (m+). 5-(3-Dodecyl-ureido)-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester. (5.5) The same method as for the preparation of 3-methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester was employed. Thus, acylation with decyl isocyanate (0.29 mL, 254 mg, 1.2 mmol) afforded 265 mg of a solid (40%) after column chromatography (9:1; hexanes:EtOAc): Mp 106.8-108.0° C.). 1H NMR (CDCl3) δ 11.04 (s, 1H), 7.45-7.26 (m, 5H), 5.27 (s, 2H), 5.24 (t, 1H, J=5.6 Hz), 3.28 (q, 2H, J=6.6 Hz), 2.72 (s, 3H), 1.60-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 18H), 0.88 (t, 3H, J=6.4 Hz). MS (EI): 559.0 (m+).

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

Procedure: Using the method of Example 2 above, but using ethyl 4-bromobutyrate, t-butyl N-[3-(ethoxycarbonyl)propyl]-N-benzyloxy carbamate was obtained as a colorless oil. This carbamate (6.17 g, 18.8 mmol) was dissolved in 3.3M HCl in ethyl acetate (50 ml) at room temperature under nitrogen. After one hour, the turbid solution was evaporated, and the residue was triturated with hexane. Filtration gave ethyl 4-(benzyloxyamino)butyrate hydrochloride as a white solid (4.59 g, 93% yield). To a solution of decyl isocyanate (0.92 g) in toluene (50 ml) was added this hydrochloride (1.40 g) in DMF (5 ml). Triethylamine (0.75 ml) was added, and the solution was stirred for one hour. The mixture was washed with 10% aqueous citric acid, and the organic solution was dried (MgSO4), filtered and evaporated. Purification by chromatography on silica gave N'-decyl-N-benzyloxy-N-[3-(ethoxycarbonylpropyl]urea as a colorless oil (1.58 g, 58% yield). The mixture was washed with 10% aqueous citric acid the organic solution was dried (MgSO4) filtered evaporated Purification by chromatography on silica

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

Procedure: To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C. The solution was refluxed for 20 minutes evaporated the residue triturated with pentane