A. (S)-( + )-2-Hydroxymethylpyrrolidine. In a 4-L, three-necked, round-bottomed flask equipped with a heating mantle (Note 1), an overhead stirrer bearing a two-bladed propeller (ca. 2.5-cm diameter), an effective reflux condenser with a drying tube packed with silica gel, and a plastic stopper are placed 2.5 L of anhydrous tetrahydrofuran (THF, (Note 2)) and 60 g (1.56 mol) of lithium aluminum hydride (LiAlH₄, (Note 3)). The suspension is heated under reflux for 15 min, the heating mantle is switched off, and 115.1 g (1 mol) of powdered (S)-proline (Note 4) is added in small portions (ca. 2 g, (Note 5)) to the boiling mixture at such a rate as to maintain reflux. The addition requires ca. 45 min and the contents of the flask are kept boiling for an additional 1 hr. Excess lithium aluminum hydride is then decomposed by cautiously adding a solution of 28 g of potassium hydroxide in 112 mL of water (without external heating) through a pressure-equalizing dropping funnel to the boiling mixture. On hydrolysis, white salts precipitate and stirring becomes difficult. After the addition is complete (ca. 25 min), the mixture is refluxed for 15 min and the hot solution is filtered by suction through a large Büchner funnel (18-cm diameter). The precipitate is pressed dry with a beaker. Any remaining prolinol is extracted from the precipitate by refluxing with 1.5 L of tetrahydrofuran for 1 hr under mechanical stirring, followed again by suction filtration. The combined filtrates are concentrated in a 2-L flask at 30°C (Note 6) under reduced pressure to yield 115–125 g of the crude hydroxymethylpyrrolidine as a pale-yellow oil.

B. (S)-(−)-1-Formyl-2-hydroxymethylpyrrolidine. The 2-L flask containing the crude hydroxymethyl derivative (ca. 1 mol) is equipped with a dropping funnel and a magnetic stirring bar and cooled to 0°C. Eighty milliliters (1.3 mol) of methyl formate (Note 7) is added over a period of 20 min and stirring is continued for 30 min at 0°C to give a green-colored solution. Excess methyl formate is evaporated at 30°C, affording a dark oil, which is taken up in 600 mL of dichloromethane and dried twice by stirring over a sufficient amount of anhydrous sodium sulfate. The drying agent is removed by suction filtration through Celite (Note 8), using a large column, and the filtrate is concentrated under reduced pressure at 30°C. Any remaining traces of solvents are removed by stirring under reduced pressure using and oil pump (20°C at 1 mm). This procedure takes about 2 hr and yields ca. 130 g (ca. 1 mol) of the dry, crude N-formyl compound, which is used in the next step without further purification.

C. (S)-(−)-1-Formyl-2-methoxymethylpyrrolidine. A 4-L, three-necked flask, fitted with a magnetic stirrer, a reflux condenser, a low-temperature thermometer, and a mineral oil bubbler is charged with a solution of the crude formyl derivative in 1.5 L of dry tetrahydrofuran (Note 9) and flushed with argon. The solution is cooled to −50 to −60°C (internal temperature, acetone–dry ice), the cooling bath is removed, and 81 mL (1.3 mol) of methyl iodide is added. Then 28.8 g (1.2 mol) of sodium hydride (Note 10) is introduced carefully in one portion.

The apparatus is flushed again with argon and allowed to warm to room temperature. During this period hydrogen gas evolves and a gray solid precipitates, which causes stirring to become difficult. At about 0°C the precipitate dissolves exothermally under strong evolution of hydrogen. The thermometer is replaced by a pressure-equalizing dropping funnel, and the solution is refluxed for 15 min and quenched by slow addition of 90 mL of 6 N hydrochloric acid, without external heating. Tetrahydrofuran is removed under reduced pressure to yield the crude O-methylated compound in water.

D. (S)-( + )-2-Methoxymethylpyrrolidine. A solution of 180 g of potassium hydroxide in 720 mL of water is added to the crude product and the mixture is vigorously stirred under argon overnight. Saturation with potassium carbonate (500 g) causes precipitation of potassium salts, which are filtered off by suction (large Büchner funnel) and washed with ether. The filtrate is extracted with ether (3 × 300 mL) (Note 11), and the ether layer is acidified with 100 mL of 12 N hydrochloric acid under ice cooling in a hood (evolution of fumes) and extracted twice with 100 mL of water to yield an aqueous solution of the hydrochloride of 2-methoxymethylpyrrolidine (Note 12).

E. (S)-(−)-1-Carbamoyl-2-methoxymethylpyrrolidine. The aqueous amine hydrochloride solution is adjusted to a pH of 2.8–3.2 (Note 13) with aqueous 50% potassium hydroxide. A solution of 80 g (1 mol) of potassium cyanate (Note 14) in 140 mL of water is then added all at once at 15°C and the mixture is allowed to stir for at least 12 hr at 20°C.

F. (S)-(−)-1-Amino-2-methoxymethylpyrrolidine (SAMP). A 4-L, three-necked flask containing the crude urea is cooled to −5°C (internal temperature) by means of an ice–salt bath and treated with a chilled (−5°C) solution of 168 g of potassium hydroxide in 150 mL of water. After addition of 685 mL (1.3 mol) of 1.9 N potassium hypochlorite solution (Note 15), precooled to −5°C, the temperature rises within 10 min to 30–40°C and the cooling bath is removed after the mixture reaches room temperature (Note 16). Stirring is continued for a total of 12–15 hr. Excess potassium hypochlorite is destroyed with a freshly prepared solution of sodium bisulfite (20 g NaHSO₃ in 50 mL of H₂O) and the mixture is acidified (pH 2) with a minimum amount of 12 N hydrochloric acid (ca. 350 mL) under ice cooling. A strong evolution of carbon dioxide occurs. The mixture is allowed to stir for an additional 15 min at ambient temperature, made alkaline (pH 9) with ca. 100 mL of aqueous 50% potassium hydroxide, and saturated with potassium carbonate (500 g). Precipitated potassium salts are filtered off by suction through a large Büchner funnel and washed twice with ethanol; the filtrate is extracted with a 1 : 1 chloroform/ethanol mixture (1 × 800 mL and 2 × 400 mL). During extraction salt precipitation again occurs and the salts should be filtered off as mentioned above. The organic layers are collected, concentrated under reduced pressure at 30°C (Note 17), taken up in 500 mL of chloroform, and dried twice over sodium sulfate. The drying agent is removed by suction filtration through Celite and the solvent is stripped off as mentioned above to give 80–90 g of a dark oil. Immediate distillation through a 40-cm vacuum-jacketed Vigreux column (the receiver should be cooled with ice to prevent loss of substance) yields a small forerun containing 2-methoxymethylpyrrolidine, followed by SAMP as a colorless liquid, bp 42°C at 1.8 mm (80°C bath temperature), [α]_D20 −79.6° (neat). Overall yields of SAMP range from 65 to 75 g (50–58%). A purity of ca. 95% was established by GLC analysis (Note 18). The optical antipode RAMP, [α]_D20 + 79.8° (neat), can be prepared likewise, starting from (R)-proline (Note 19).