Methyl aminolevulinate hydrochloride

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

Procedure: Pyrrolidine-1,2-dicarboxylic acid 2-tert-butyl ester 1-(2,5-dioxo-pyrrolidin-1-yl) ester (1.03 g, 3.3 mmol) was dissolved in DMF (30 mL) and 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride salt (0.60 g, 3.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Triethylamine was added and stirring continued overnight (ca. 16 h). The reaction was poured into water (300 mL) and extracted with ethyl acetate (3×70 mL). The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL). The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1) to give the title compound (0.57 g, 50%). 1HNMR (400 MHz, CDCl3): δ4.2 (m, 3H), 3.65 (s, 3H), 3.43 (m, 1.5H), 3.35 (m, 0.5H), 2.70 (m, 2H), 2.62 (m, 2H), 2.25 (bs, 0.25H), 2.15 (bs, 0.75H), 1.88 (m, 2H), 1.70 (bs, 1H), 1.25 (bs, 9H). MS: Calc'd for C11H18N2O4 (M-BOC): 242.13. Found (M-BOC+1): 243.0. stirring continued overnight (ca. 16 h) extracted with ethyl acetate (3×70 mL) The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL) The organic portion was dried over magnesium sulfate the solvent removed in vacuo The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1)

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

Procedure: Methyl hydrogen isophthalate (1.8 g, 10.2 mmol) is dissolved in methylene chloride (10 mL) and DMF (10 mL), and diisopropylethylamine (4.4 mL, 25.5 mmol), HATU (4.6 g, 12.2 mmol), and 5-aminolevulinic acid methyl ester hydrochloride (2 g, 11.2 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 4% methanol/chloroform) provides the title compound. ESI MS m/z 306.1 [M−H]−. The reaction is partitioned between ethyl acetate and water The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 4% methanol/chloroform)

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

Procedure: Pyrrolidine-1,2-dicarboxylic acid 2-tert-butyl ester 1-(2,5-dioxo-pyrrolidin-1-yl) ester (1.03 g, 3.3 mmol) was dissolved in DMF (30 mL) and 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride salt (0.60 g, 3.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Triethylamine was added and stirring continued overnight (ca. 16 h). The reaction was poured into water (300 mL) and extracted with ethyl acetate (3×70 mL). The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL). The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1) to give the title compound (0.57 g, 50%). 1HNMR (400 MHz, CDCl3): δ4.2 (m, 3H), 3.65 (s, 3H), 3.43 (m, 1.5H), 3.35 (m, 0.5H), 2.70 (m, 2H), 2.62 (m, 2H), 2.25 (bs, 0.25H), 2.15 (bs, 0.75H), 1.88 (m, 2H), 1.70 (bs, 1H), 1.25 (bs, 9H). MS: Calc'd for C11H18N2O4 (M-BOC): 242.13. Found (M-BOC+1): 243.0. stirring continued overnight (ca. 16 h) extracted with ethyl acetate (3×70 mL) The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL) The organic portion was dried over magnesium sulfate the solvent removed in vacuo The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1)

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

Procedure: Pyrrolidine-1,2-dicarboxylic acid 2-tert-butyl ester 1-(2,5-dioxo-pyrrolidin-1-yl) ester (1.03 g, 3.3 mmol) was dissolved in DMF (30 mL) and 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride salt (0.60 g, 3.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Triethylamine was added and stirring continued overnight (ca. 16 h). The reaction was poured into water (300 mL) and extracted with ethyl acetate (3×70 mL). The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL). The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1) to give the title compound (0.57 g, 50%). 1HNMR (400 MHz, CDCl3): δ4.2 (m, 3H), 3.65 (s, 3H), 3.43 (m, 1.5H), 3.35 (m, 0.5H), 2.70 (m, 2H), 2.62 (m, 2H), 2.25 (bs, 0.25H), 2.15 (bs, 0.75H), 1.88 (m, 2H), 1.70 (bs, 1H), 1.25 (bs, 9H). MS: Calc'd for C11H18N2O4 (M-BOC): 242.13. Found (M-BOC+1): 243.0. stirring continued overnight (ca. 16 h) extracted with ethyl acetate (3×70 mL) The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL) The organic portion was dried over magnesium sulfate the solvent removed in vacuo The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml glass reactor containing 200 ml methanol, was added 1 gram 5-amino-levulinic acid hydrochloride and 1 drop conc. HCl. The reaction mixture was then stirred overnight at 60° C. The progress of the esterification was followed by 1H-NMR. Excess methanol was removed by distillation, and the product further dried under vacuum at 30-40° C., giving methyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6. Excess methanol was removed by distillation the product further dried under vacuum at 30-40° C.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml glass reactor containing 200 ml methanol, was added 1 gram 5-amino-levulinic acid hydrochloride and 1 drop conc. HCl. The reaction mixture was then stirred overnight at 60° C. The progress of the esterification was followed by 1H-NMR. Excess methanol was removed by distillation, and the product further dried under vacuum at 30-40° C., giving methyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6. Excess methanol was removed by distillation the product further dried under vacuum at 30-40° C.

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

Procedure: Pyrrolidine-1,2-dicarboxylic acid 2-tert-butyl ester 1-(2,5-dioxo-pyrrolidin-1-yl) ester (1.03 g, 3.3 mmol) was dissolved in DMF (30 mL) and 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride salt (0.60 g, 3.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Triethylamine was added and stirring continued overnight (ca. 16 h). The reaction was poured into water (300 mL) and extracted with ethyl acetate (3×70 mL). The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL). The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1) to give the title compound (0.57 g, 50%). 1HNMR (400 MHz, CDCl3): δ4.2 (m, 3H), 3.65 (s, 3H), 3.43 (m, 1.5H), 3.35 (m, 0.5H), 2.70 (m, 2H), 2.62 (m, 2H), 2.25 (bs, 0.25H), 2.15 (bs, 0.75H), 1.88 (m, 2H), 1.70 (bs, 1H), 1.25 (bs, 9H). MS: Calc'd for C11H18N2O4 (M-BOC): 242.13. Found (M-BOC+1): 243.0. stirring continued overnight (ca. 16 h) extracted with ethyl acetate (3×70 mL) The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL) The organic portion was dried over magnesium sulfate the solvent removed in vacuo The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1)

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

Procedure: Pyrrolidine-1,2-dicarboxylic acid 2-tert-butyl ester 1-(2,5-dioxo-pyrrolidin-1-yl) ester (1.03 g, 3.3 mmol) was dissolved in DMF (30 mL) and 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride salt (0.60 g, 3.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Triethylamine was added and stirring continued overnight (ca. 16 h). The reaction was poured into water (300 mL) and extracted with ethyl acetate (3×70 mL). The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL). The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1) to give the title compound (0.57 g, 50%). 1HNMR (400 MHz, CDCl3): δ4.2 (m, 3H), 3.65 (s, 3H), 3.43 (m, 1.5H), 3.35 (m, 0.5H), 2.70 (m, 2H), 2.62 (m, 2H), 2.25 (bs, 0.25H), 2.15 (bs, 0.75H), 1.88 (m, 2H), 1.70 (bs, 1H), 1.25 (bs, 9H). MS: Calc'd for C11H18N2O4 (M-BOC): 242.13. Found (M-BOC+1): 243.0. stirring continued overnight (ca. 16 h) extracted with ethyl acetate (3×70 mL) The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL) The organic portion was dried over magnesium sulfate the solvent removed in vacuo The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1)

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

Procedure: Methyl hydrogen isophthalate (1.8 g, 10.2 mmol) is dissolved in methylene chloride (10 mL) and DMF (10 mL), and diisopropylethylamine (4.4 mL, 25.5 mmol), HATU (4.6 g, 12.2 mmol), and 5-aminolevulinic acid methyl ester hydrochloride (2 g, 11.2 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 4% methanol/chloroform) provides the title compound. ESI MS m/z 306.1 [M−H]−. The reaction is partitioned between ethyl acetate and water The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 4% methanol/chloroform)

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

Procedure: Methyl hydrogen isophthalate (1.8 g, 10.2 mmol) is dissolved in methylene chloride (10 mL) and DMF (10 mL), and diisopropylethylamine (4.4 mL, 25.5 mmol), HATU (4.6 g, 12.2 mmol), and 5-aminolevulinic acid methyl ester hydrochloride (2 g, 11.2 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 4% methanol/chloroform) provides the title compound. ESI MS m/z 306.1 [M−H]−. The reaction is partitioned between ethyl acetate and water The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 4% methanol/chloroform)

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

Procedure: Pyrrolidine-1,2-dicarboxylic acid 2-tert-butyl ester 1-(2,5-dioxo-pyrrolidin-1-yl) ester (1.03 g, 3.3 mmol) was dissolved in DMF (30 mL) and 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride salt (0.60 g, 3.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Triethylamine was added and stirring continued overnight (ca. 16 h). The reaction was poured into water (300 mL) and extracted with ethyl acetate (3×70 mL). The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL). The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1) to give the title compound (0.57 g, 50%). 1HNMR (400 MHz, CDCl3): δ4.2 (m, 3H), 3.65 (s, 3H), 3.43 (m, 1.5H), 3.35 (m, 0.5H), 2.70 (m, 2H), 2.62 (m, 2H), 2.25 (bs, 0.25H), 2.15 (bs, 0.75H), 1.88 (m, 2H), 1.70 (bs, 1H), 1.25 (bs, 9H). MS: Calc'd for C11H18N2O4 (M-BOC): 242.13. Found (M-BOC+1): 243.0. stirring continued overnight (ca. 16 h) extracted with ethyl acetate (3×70 mL) The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 mL), water (2×30 mL), and brine (50 mL) The organic portion was dried over magnesium sulfate the solvent removed in vacuo The resulting yellow oil was chromatographed on a Biotage 40S column with ethyl acetate: hexanes (4:1)

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

Procedure: A 30 g (165 mmol) portion of δ-aminolevulinic acid methyl ester hydrochloride and 20.9 g (181 mmol) of 85% phosphoric acid were dissolved in 30 ml of purified water, and 17.5 g (173 mmol) of triethylamine was added dropwise thereto while stirring on an ice bath. After completion of the dropwise addition and subsequent stirring at room temperature for 10 minutes, 400 ml of ethanol was added thereto and stirred. The thus precipitated precipitate was recovered by suction filtration and dried at room temperature for 17 hours under a reduced pressure. A 37 g (154 mmol) portion of δ-aminolevulinic acid methyl ester phosphate was obtained at a yield of 93 mol %. After completion of the dropwise addition subsequent stirring at room temperature for 10 minutes stirred The thus precipitated precipitate was recovered by suction filtration dried at room temperature for 17 hours under a reduced pressure