2-[2-(2-methoxyethoxy)ethoxy]acetic acid

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams (0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for 45 minutes. The reaction mixture was cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acid chloride was assumed. Upon completion of addition the reaction mixture was warmed to reflux where it The reaction mixture was cooled

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

Procedure: To a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.6 g, 3.34 mmol), TBTU (1.2 g, 4.0 mmol) and DIPEA (1.3 ml, 4.0 mmol) in DMF (20 ml) was added 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (1.0 g, 3.34 mmol). The resulting mixture was stirred for 18 hr at room temperature. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (2×100 ml), brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave Example 77 as a colorless oil. Yield (0.7 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J=5.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 6.82-6.85 (m, 2H), 6.72-6.75 (m, 1H), 5.22 (d, J=4.8 Hz, 1H), 4.48-4.52 (m, 1H), 3.82 (s, 2H), 3.72 (d, J=6.4 Hz, 2H), 3.42-3.52 (m, 2H), 3.39-3.41 (m, 2H), 3.30 (s, 3H), 3.12-3.17 (m, 2H), 2.86 (s, 2H), 2.66 (s, 2H), 1.61-1.79 (m, 8H), 1.08-1.28 (m, 3H), 0.98-1.06 (m, 2H). washed with water (2×100 ml), brine (100 ml) dried (Na2SO4) concentrated under reduced pressure Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)

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

Procedure: To a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.6 g, 3.34 mmol), TBTU (1.2 g, 4.0 mmol) and DIPEA (1.3 ml, 4.0 mmol) in DMF (20 ml) was added 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (1.0 g, 3.34 mmol). The resulting mixture was stirred for 18 hr at room temperature. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (2×100 ml), brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave Example 77 as a colorless oil. Yield (0.7 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J=5.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 6.82-6.85 (m, 2H), 6.72-6.75 (m, 1H), 5.22 (d, J=4.8 Hz, 1H), 4.48-4.52 (m, 1H), 3.82 (s, 2H), 3.72 (d, J=6.4 Hz, 2H), 3.42-3.52 (m, 2H), 3.39-3.41 (m, 2H), 3.30 (s, 3H), 3.12-3.17 (m, 2H), 2.86 (s, 2H), 2.66 (s, 2H), 1.61-1.79 (m, 8H), 1.08-1.28 (m, 3H), 0.98-1.06 (m, 2H). washed with water (2×100 ml), brine (100 ml) dried (Na2SO4) concentrated under reduced pressure Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)

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

Procedure: Example 160, [M+H]+ 868.5, was prepared in a manner analogous to Example 147 starting from N-tert-butyl-2-[3(S)-[[N-(3-cyanobenzoyl)-3-(methanesulfonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-3(S)-isoquinolinecarboxamide (Example 39) and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich 40,7000-3).

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

Procedure: Example 160, [M+H]+ 868.5, was prepared in a manner analogous to Example 147 starting from N-tert-butyl-2-[3(S)-[[N-(3-cyanobenzoyl)-3-(methanesulfonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-3(S)-isoquinolinecarboxamide (Example 39) and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich 40,7000-3).

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

Procedure: To a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.6 g, 3.34 mmol), TBTU (1.2 g, 4.0 mmol) and DIPEA (1.3 ml, 4.0 mmol) in DMF (20 ml) was added 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (1.0 g, 3.34 mmol). The resulting mixture was stirred for 18 hr at room temperature. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (2×100 ml), brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave Example 77 as a colorless oil. Yield (0.7 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J=5.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 6.82-6.85 (m, 2H), 6.72-6.75 (m, 1H), 5.22 (d, J=4.8 Hz, 1H), 4.48-4.52 (m, 1H), 3.82 (s, 2H), 3.72 (d, J=6.4 Hz, 2H), 3.42-3.52 (m, 2H), 3.39-3.41 (m, 2H), 3.30 (s, 3H), 3.12-3.17 (m, 2H), 2.86 (s, 2H), 2.66 (s, 2H), 1.61-1.79 (m, 8H), 1.08-1.28 (m, 3H), 0.98-1.06 (m, 2H). washed with water (2×100 ml), brine (100 ml) dried (Na2SO4) concentrated under reduced pressure Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)

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

Procedure: To a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.6 g, 3.34 mmol), TBTU (1.2 g, 4.0 mmol) and DIPEA (1.3 ml, 4.0 mmol) in DMF (20 ml) was added 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (1.0 g, 3.34 mmol). The resulting mixture was stirred for 18 hr at room temperature. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (2×100 ml), brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave Example 77 as a colorless oil. Yield (0.7 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J=5.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 6.82-6.85 (m, 2H), 6.72-6.75 (m, 1H), 5.22 (d, J=4.8 Hz, 1H), 4.48-4.52 (m, 1H), 3.82 (s, 2H), 3.72 (d, J=6.4 Hz, 2H), 3.42-3.52 (m, 2H), 3.39-3.41 (m, 2H), 3.30 (s, 3H), 3.12-3.17 (m, 2H), 2.86 (s, 2H), 2.66 (s, 2H), 1.61-1.79 (m, 8H), 1.08-1.28 (m, 3H), 0.98-1.06 (m, 2H). washed with water (2×100 ml), brine (100 ml) dried (Na2SO4) concentrated under reduced pressure Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient)

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

Procedure: Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams (0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for 45 minutes. The reaction mixture was cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acid chloride was assumed. Upon completion of addition the reaction mixture was warmed to reflux where it The reaction mixture was cooled

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

Procedure: Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams (0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for 45 minutes. The reaction mixture was cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acid chloride was assumed. Upon completion of addition the reaction mixture was warmed to reflux where it The reaction mixture was cooled

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

Procedure: Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams (0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for 45 minutes. The reaction mixture was cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acid chloride was assumed. Upon completion of addition the reaction mixture was warmed to reflux where it The reaction mixture was cooled

Conditions: temp:0.00; pressure:0.00; stir: