ethyl (2S)-2-hydroxypropanoate

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

Procedure: Diethylazodicarboxylate (8.66 ml) in dry tetrahydrofuran (25 ml) was added dropwise over 30 minutes to a stirred solution of triphenylphosphine (13.11 g), (S)-(−)-ethyl lactate (5.67 ml) and 4-phenylphenol (8.51 g) in dry tetrahydrofuran (100 ml). The resulting solution was stirred at room temperature for 18 hours then concentrated under reduced pressure. A mixture of isohexane: ether (9:1) (200 ml) was added to the residue and stirred at room temperature for 30 minutes. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane : dichloromethane (2:3) to give the sub-title compound as an oil (11.79 g). then concentrated under reduced pressure A mixture of isohexane: ether (9:1) (200 ml) was added to the residue stirred at room temperature for 30 minutes The solution was filtered the filtrate concentrated under reduced pressure The residue was purified by column chromatography over silica eluting with isohexane : dichloromethane (2:3)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask charged with piperazine (10.0 g, 116 mmol) and (S)-ethyl 2-hydroxypropanoate 7 (17.84 g, 151 mmol, 1.30 equiv) was cooled to 10° C. Sodium methoxide (25 wt % in MeOH) (12.55 g, 58.1 mmol, 0.50 equiv) was slowly added while maintaining the temperature below 20° C. The cold water bath was removed and the reaction mixture was allowed to warm to ambient temperature and aged for 19 h. Water (6.23 g, 346 mmol, 3.0 equiv) was added and the mixture was aged for 16 h. The mixture was diluted with ethanol (40 mL) and concentrated under reduced pressure. The residue was diluted with ethanol (40 mL) and treated with a solution of oxalic acid dihydrate (6.58 g, 52.2 mmol) in ethanol (30 mL) to adjust the pH to 7.5. The suspension was cooled to <10° C., filtered through a pad of CELITE® and washed with ethanol (2×60 mL). The filtrate and washes were combined and concentrated to 50 mL. The solution was cooled to 10° C. and a solution of oxalic acid dihydrate (16.1 g, 128 mmol) in ethanol (60 mL) was slowly added. The suspension was allowed to warm to ambient temperature and stirred for 1 h. The suspension was cooled to 10° C. and the solid was collected by filtration, washed with cold ethanol (2×18 mL) and dried under reduced pressure at 50° C. for 24 h to afford the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V as a white solid (15.2 g, 53%). 1H NMR (300 MHz, D2O) δ 4.73-4.51 (m, 1H), 3.93-3.59 (m, 4H), 3.26 (dd, J=8.8, 4.0 Hz, 4H), 1.27 (d, J=6.7 Hz, 3H). while maintaining the temperature below 20° C The cold water bath was removed to warm to ambient temperature and aged for 19 h concentrated under reduced pressure The residue was diluted with ethanol (40 mL) The suspension was cooled to <10° C. filtered through a pad of CELITE® washed with ethanol (2×60 mL) concentrated to 50 mL The solution was cooled to 10° C. to warm to ambient temperature The suspension was cooled to 10° C. the solid was collected by filtration washed with cold ethanol (2×18 mL) dried under reduced pressure at 50° C. for 24 h

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

Procedure: Scheme 4 shows the synthesis of intermediate (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V from (S)-ethyl 2-hydroxypropanoate 7. 1-Benzylpiperazine and 7 were reacted in sodium methoxide and methanol to give (S)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one 8, isolated from AMBERLITE® IRC-748 resin or oxalic acid, followed by the activated charcoal treatment (Example 10). Reductive cleavage removal of the benzyl group from 8 was effected by palladium catalysis with either hydrogen gas (Method A) or cyclohexene (Method B) to give intermediate (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one 6 (Example 11). The oxalate salt was formed from 6 with oxalic acid in ethanol and tetrahydrofuran to give V (Example 11).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance. The reaction solution was concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance. The reaction solution was concentrated

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

Procedure: Trifluoromethanesulfonic acid (1.13 g) was added to a stirred mixture of ethyl (S)-(−)-lactate (5.90 g) and benzyl 2,2,2-trichloroacetimidate (15.15 g) in cyclohexane (70 ml) and methylene chloride (35 ml) at room temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was filtered. The filtrate was diluted with cyclohexane, and then washed successively with saturated NaHCO3 solution (100 ml)and H2O (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1) to give ethyl (S)-2-(benzyloxy)propionate (6.48 g). the reaction mixture was filtered The filtrate was diluted with cyclohexane washed successively with saturated NaHCO3 solution (100 ml)and H2O (100 ml) The organic layer was dried over sodium sulfate concentrated in vacuo The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1)

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

Procedure: Trifluoromethanesulfonic acid (1.13 g) was added to a stirred mixture of ethyl (S)-(−)-lactate (5.90 g) and benzyl 2,2,2-trichloroacetimidate (15.15 g) in cyclohexane (70 ml) and methylene chloride (35 ml) at room temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was filtered. The filtrate was diluted with cyclohexane, and then washed successively with saturated NaHCO3 solution (100 ml)and H2O (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1) to give ethyl (S)-2-(benzyloxy)propionate (6.48 g). the reaction mixture was filtered The filtrate was diluted with cyclohexane washed successively with saturated NaHCO3 solution (100 ml)and H2O (100 ml) The organic layer was dried over sodium sulfate concentrated in vacuo The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1)

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

Procedure: To a solution of {4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonic acid monophenyl ester (25 mg, 0.048 mmol) and ethyl (S)-(−)-lactate (34 mg, 0.288 mmol) in pyridine (1 mL) was added PyBOP (125 mg, 0.24 mmol). The solution was stirred at room temperature for 16 hours and concentrated. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24 mg (83%) of the desired product. MS (m/z) 641 [M+Na]+. concentrated The residue was purified by RP HPLC

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

Procedure: To a solution of {4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonic acid monophenyl ester (25 mg, 0.048 mmol) and ethyl (S)-(−)-lactate (34 mg, 0.288 mmol) in pyridine (1 mL) was added PyBOP (125 mg, 0.24 mmol). The solution was stirred at room temperature for 16 hours and concentrated. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24 mg (83%) of the desired product. MS (m/z) 641 [M+Na]+. concentrated The residue was purified by RP HPLC

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

Procedure: To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl ester (18.5 mg, 0.040 mmol) and ethyl (S)-(−)-lactate (47 μL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060 mmol). The solution was stirred at room temperature for 1 hour, when an additional portion of PyBOP (21 mg, 0.040 mmol) was added. The solution was stirred for another hour and concentrated. The residue was purified by HPLC to provide 7.5 mg of the desired product as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.22 and 1.25 (t, 3H, J=7 Hz), 1.42 and 1.50 (d, 3H, J=7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.78 (s, 3H), 3.89 (d, 1H, J=8 Hz), 3.93-4.02 (m, 3H), 4.10-4.22 (m, 2H), 4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15-7.27 (m, 3H), 7.33-7.41 (m, 2H) ppm; 31P (121.4 MHz, CD3OD) δ 18.9, 20.3 ppm (diastereomers at phosphorus); MS (m/z) 549.2 [M+H]+, 571.3 [M+Na]+. The solution was stirred for another hour concentrated The residue was purified by HPLC

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

Procedure: To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl ester (18.5 mg, 0.040 mmol) and ethyl (S)-(−)-lactate (47 μL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060 mmol). The solution was stirred at room temperature for 1 hour, when an additional portion of PyBOP (21 mg, 0.040 mmol) was added. The solution was stirred for another hour and concentrated. The residue was purified by HPLC to provide 7.5 mg of the desired product as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.22 and 1.25 (t, 3H, J=7 Hz), 1.42 and 1.50 (d, 3H, J=7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.78 (s, 3H), 3.89 (d, 1H, J=8 Hz), 3.93-4.02 (m, 3H), 4.10-4.22 (m, 2H), 4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15-7.27 (m, 3H), 7.33-7.41 (m, 2H) ppm; 31P (121.4 MHz, CD3OD) δ 18.9, 20.3 ppm (diastereomers at phosphorus); MS (m/z) 549.2 [M+H]+, 571.3 [M+Na]+. The solution was stirred for another hour concentrated The residue was purified by HPLC

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

Procedure: A solution of 2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol) and PyBOP (234 mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate (53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperature for 1 hour, when complete consumption of the starting materials was observed. The reaction was worked up by addition of saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated and washed with 5% aqueous solution of lithium chloride. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (0-20%) to provide 57 mg (74%) of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7 Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz), 3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9 Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 28.9, 29.9 ppm; MS (m/z) 791.4 [M+Na]+. when complete consumption of the starting materials The reaction was worked up by addition of saturated aqueous sodium chloride and ethyl acetate The organic layer was separated washed with 5% aqueous solution of lithium chloride The organic layer was dried in vacuo the residue was purified by silica gel chromatography