SYNTHESIS OF ᴅⳑ-PROLINE (ᴅⳑ-Pyrrolidine-2-carboxylic acid)

3-Ethoxycarbonyl-2-piperidone: 

• Dissolve 160g (0.75 mol) of diethyl (2- cyanoethyl)malonate in 600 ml of ethanol and hydrogenate in the presence of about 4-5 g of Raney nickel catalyst at 80 °C and 75 atmospheres pressure of hydrogen in an autoclave; uptake of hydrogen is complete in about 2 hours. 

• Remove the catalyst by filtration and the solvent by distillation under reduced pressure (rotary evaporator) and pour the residue with stirring into 500 ml of light petroleum (b.p. 60-80 °C). 

• Filter off the precipitated piperidone and allow it to dry in the air; yield 115g (90%), m.p. 74 °C. A specimen crystallised from ethanol/light petroleum has m.p. 80 °C.

3-ChIoro-3-ethoxycarbonyI-2-piperidone:

• Assemble in a fume cupboard a 500-ml three-necked flask fitted with a sealed stirrer unit, a dropping funnel and a reflux condenser protected by a calcium chloride guard-tube. 

• Charge the flask with a solution of 111g (0.65 mol) of 3-ethoxycarbonyl-2-piperidone in 175 ml of dry chloroform (CAUTION), and the dropping funnel with 90g (54 ml, 0.67 mol) of redistilled sulphuryl chloride dissolved in 125 ml of dry chloroform; close the neck of the funnel with a calcium chloride guard-tube. 

• Start the stirrer, and slowly run in the solution of sulphuryl chloride so that the reaction mixture refluxes gently. 

• When the addition is complete, warm on a steam bath until hydrogen chloride .evolution ceases. 

• Remove the solvent under reduced pressure using a rotary evaporator, and cool the residue, scratching the sides of the flask to induce crystallisation.

•  Dissolve the solid in 70 ml of hot ethyl acetate, add hot light petroleum (b.p. 80-100 °C) until the solution is slightly turbid, and cool while scratching the side of the vessel vigorously until the product crystallises (it helps to add a few crystals of the crude solid as a seed). 

• Add 30 ml more of light petroleum, cool further and filter. The chloropiperidone is obtained as a somewhat sticky white solid, m.p. 64-68 °C; yield is 100g (82%).

ᴅⳑ-Proline hydrochloride:

• Boil 103g (0.5 mol) of the above chloropiperidone under reflux with 200 ml of concentrated hydrochloric acid (fume cupboard) for 5 hours during which time decarboxylation ensues. 

• Boil the solution with about 2g of decolourising charcoal (acid-washed grade), filter and evaporate under reduced pressure using a rotary evaporator; dissolve the residue in water and re-evaporate to assist the removal of most of the excess hydrochloric acid. 

• Dissolve the resulting pale golden syrup in 80 ml of water, add a solution of 60g of sodium hydroxide in 120 ml of water and leave at room temperature for 2 days. 

• Acidify the solution to Congo red paper with concentrated hydrochloric acid (about 130 ml are needed) and evaporate to dryness under reduced pressure (rotary evaporator). 

• Dry the resulting solid completely by leaving it overnight in a vacuum desiccator over phosphorus pentoxide and potassium hydroxide pellets, and then extract it with 200 ml of boiling absolute ethanol. 

• Filter off the sodium chloride and re-extract it with 150 ml more of boiling ethanol. 

• Evaporate the ethanol from the combined filtrates and boil the residue under reflux for 1 hour with 1.25 litres of 2ᴍ hydrochloric acid to hydrolyse any proline ester formed in the extraction process. 

• Evaporate to dryness, redissolve the residue in water and re-evaporate, and dry the resulting crude ᴅⳑ-proline hydrochloride in a vacuum desiccator over phosphorus pentoxide and potassium hydroxide; the yield is 70g. 

• Recrystallise the product from 175 ml of hot propan-2-ol, cool in ice, filter and wash the crystals with 20 ml of ice-cold propan-2-ol. The yield of the purified product, m.p. 148-150 °C, is 50g (66%).

Conversion to ᴅⳑ-proline:

• Suspend 15g (0.1 mol) of dry proline hydrochloride in 70 ml of dry chloroform, stir vigorously and run in dropwise 15g (0. 15 mol) of dried, redistilled triethylamine. 

• Continue stirring for 1 hour, filter off the product and wash it with a little cold chloroform. The yield of ᴅⳑ-proline is 10g (87%); a sample crystallised from absolute ethanol has m.p. 206-207 °C (with preliminary sintering).