(1-chloro-2-methylpropyl) carbonochloridate

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

Procedure: To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing 1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0° C. and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 mL) and the organic layer separated. The aqueous layer was further extracted with ether (3×20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vacuo. Chromatography of the residue on silica gel, eluting with hexane: ethyl acetate (1:4) gave 2.37 g (77%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H+). was then added at 0° C. stirred at room temperature for 60 min The reaction mixture was washed with 10% citric acid (30 mL) the organic layer separated The aqueous layer was further extracted with ether (3×20 mL) the combined organic phases were dried over MgSO4 concentrated in vacuo Chromatography of the residue on silica gel, eluting with hexane: ethyl acetate (1:4)

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

Procedure: To a solution of 0.75 g of ethyl 4-[[2-oxo-4-(piperidin-4-yl)-piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 16 ml of methylene chloride was added 1.11 g of proton sponge under ice-cooling. After stirring for 5 minutes, the mixture was cooled to −40° C., and a solution of 0.322 g of 1-chloro-2-methylpropyl chloroformate in 2 ml of methylene chloride. After stirring for 45 minutes, the reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layer collected was washed with saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1-40:1) to give 0.624 g (74%) of ethyl 4-[[4-[1-(1-chloroethoxycarbonyl)piperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate. cooling After stirring for 45 minutes the organic layer was separated The aqueous layer was extracted with ethyl acetate The organic layer collected was washed with saturated aqueous saline dried over sodium sulfate the solvent was removed by distillation The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1-40:1)

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

Procedure: In a manner similar to the method described in Example 3, 1-chloro-2-methylpropyl chloroformate (Aldrich) was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloro-2-methylpropyl 2-(2-(2-methoxyethoxy)-ethoxy)ethyl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 15-methyl-12-oxo-2,5,8,11,13-pentaoxahexadecan-14-yl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C43H52Cl2F2N3O10: [(M+H)+]: 878, found: 878.

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

Procedure: In a manner similar to the method described in Example 3, 1-chloro-2-methylpropyl chloroformate (Aldrich) was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloro-2-methylpropyl 2-(2-(2-methoxyethoxy)-ethoxy)ethyl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 15-methyl-12-oxo-2,5,8,11,13-pentaoxahexadecan-14-yl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C43H52Cl2F2N3O10: [(M+H)+]: 878, found: 878.

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

Procedure: To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing 1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0° C. and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 mL) and the organic layer separated. The aqueous layer was further extracted with ether (3×20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vacuo. Chromatography of the residue on silica gel, eluting with hexane: ethyl acetate (1:4) gave 2.37 g (77%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H+). was then added at 0° C. stirred at room temperature for 60 min The reaction mixture was washed with 10% citric acid (30 mL) the organic layer separated The aqueous layer was further extracted with ether (3×20 mL) the combined organic phases were dried over MgSO4 concentrated in vacuo Chromatography of the residue on silica gel, eluting with hexane: ethyl acetate (1:4)

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

Procedure: To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing 1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0° C. and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 mL) and the organic layer separated. The aqueous layer was further extracted with ether (3×20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vacuo. Chromatography of the residue on silica gel, eluting with hexane:ethyl acetate (1:4) gave 2.37 g (77%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H+). was then added at 0° C. stirred at room temperature for 60 min The reaction mixture was washed with 10% citric acid (30 mL) the organic layer separated The aqueous layer was further extracted with ether (3×20 mL) the combined organic phases were dried over MgSO4 concentrated in vacuo Chromatography of the residue on silica gel, eluting with hexane:ethyl acetate (1:4)

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

Procedure: Following the general procedure for the one pot synthesis, sarcosine (1.0 g, 11.2 mmol) was reacted with chlorotrimethylsilane (2.8 mL, 22.4 mmol) in anhydrous chloroform (25 mL) in the presence of DIEA (4.1 mL, 22.4 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (4.59 g, 22.4 mmol) followed by a mixture of DIEA (4.1 mL, 22.4 mmol) and benzoic acid (2.8 g, 22.4 mmol) provided 0.622 g (16.3% yield) of the title compound (50) as a buff-colored solid after aqueous work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=8.13 (d, 2H), 7.81 (d, 1H), 7.61 (m, 3H), 7.57 (m, 5H), 4.10 (br m, 2H), 3.01 (2s, 3H). MS (ESI) m/z 366.14 (M+Na)+.

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

Procedure: Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and admantane carboxylic acid (3.5 g, 19.7 mmol) provided 0.220 g (6.4% yield) of the title compound (22) as a white solid after aqueous work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.81 (q, 1H), 5.62 (s, 0.2H), 5.38 (s, 0.8H), 2.09 (m, 4H), 1.93 (m, 6H), 1.72 (m, 6H), 1.61 (s, 2H), 1.52 (d, 3H), 1.37 (br s, 2H). MS (ESI) m/z 374.01 (M+H)+, M−H=350.04 (M−H)−.

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

Procedure: Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and admantane carboxylic acid (3.5 g, 19.7 mmol) provided 0.220 g (6.4% yield) of the title compound (22) as a white solid after aqueous work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.81 (q, 1H), 5.62 (s, 0.2H), 5.38 (s, 0.8H), 2.09 (m, 4H), 1.93 (m, 6H), 1.72 (m, 6H), 1.61 (s, 2H), 1.52 (d, 3H), 1.37 (br s, 2H). MS (ESI) m/z 374.01 (M+H)+, M−H=350.04 (M−H)−.

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

Procedure: Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and p-toluic acid (2.6 g, 19.7 mmol) provided 0.436 g (14.3% yield) the title compound (21) as a white solid after aqueous work-up and mass-guided preparative HPLC purification. M.p: 177.7-182.5° C. 1H NMR (CDCl3, 400 MHz): δ=7.91 (d, 2H), 7.22 (m, 4H), 7.02 (q, 1H), 5.38 (s, 1H), 2.43 (s, 3H), 1.63 (m, 5H) 1.36 (m, 2H). MS (ESI) m/z 329.93 (M+H)+; 305.97 (M−H)−.

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

Procedure: Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and phenylacetic acid (2.6 g, 19.7 mmol) provided 0.560 g (14.4% yield) the title compound (20) as a yellow solid after aqueous work-up and mass-guided preparative HPLC purification. M.p: 142.1-145.6° C. 1H NMR (CDCl3, 400 MHz): δ=7.33 (m, 5H), 6.81 (q, 1H), 5.31 (s, 1H), 3.61 (s, 2H), 1.63 (m, 2H), 1.47 (d, 3H), 1.28 (m, 2H). MS (ESI) m/z 330.08 (M+Na)+.

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

Procedure: Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and phenylacetic acid (2.6 g, 19.7 mmol) provided 0.560 g (14.4% yield) the title compound (20) as a yellow solid after aqueous work-up and mass-guided preparative HPLC purification. M.p: 142.1-145.6° C. 1H NMR (CDCl3, 400 MHz): δ=7.33 (m, 5H), 6.81 (q, 1H), 5.31 (s, 1H), 3.61 (s, 2H), 1.63 (m, 2H), 1.47 (d, 3H), 1.28 (m, 2H). MS (ESI) m/z 330.08 (M+Na)+.