Introduction
The Diethyl phenylmalonate synthesis pathway is represented in this topic. Diethyl phenylmalonate is obtained from Ethyl phenylacetate (CAS 101-97-3), which isn't included in controlled precursor list of International Narcotics Control Board (INCB). Diethyl phenylmalonate is used for Phenobarbital direct synthesis.
Equipment and glassware:
- 2 L three-necked flask;
- Retort stand and clamp for securing apparatus;
- Magnetic or top stirrer with heater;
- 250 mL Drip funnel;
- Vacuum source;
- Glass rod and spatula;
- Rotovap machine;
- Reflux condenser;
- Laboratory scale (0.001-500 g is suitable) [depends on synthesis load];
- Laboratory grade thermometer (10 °C to 200 °C) with flask adapter;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- Water and mineral oil/sand bath;
- 2 L x1; 500 mL x2; 100 mL x2 Beakers;
- 1 L Measuring cylinder;
- 500 mL Claisen flask having a fractionating side arm;
- Boiling chips;
- Vacuum distillation apparatus with Manometer (optional);
- Bubbler;
Reagents:
- 600 mL Absolute ethyl alcohol (EtOH);
- 23 g (1 mole) Sodium (Na);
- 146 g (1 mole) Ethyl oxalate (2);
- 175 g (1.06 moles) Ethyl phenylacetate (1);
- 1.3 L Diethyl ether (Et2O);
- 29 mL Sulfuric acid conc. (H2SO4);
- 500 mL Distilled water (H2O);
- ~200 g Sodium sulfate (Na2SO4) or magnesium sulphate (MgSO4) [anhydrous];
1,3-Diethyl 2-phenylpropanedioate:
Boiling Point: 171 °C at 21 torr;
Melting Point: 16.5 °C;
Molecular Weight: 236.26 g/mol;
Density: 1.101 g/mL (15 °C);
CAS Number: 83-13-6.
Procedure
In a 2 L three-necked flask, fitted with a stirrer, reflux condenser, and dropping funnel, is placed 500 mL of absolute ethyl alcohol (EtOH) (Note 1), and 23 g (1 mole) of cleanly cut sodium is added in portions. When the sodium has dissolved, the solution is cooled to 60 °C, and 146 g (1 mole) of ethyl oxalate (2) (Note 2) is added in a rapid stream through the drip funnel with vigorous stirring. This is washed down with a small quantity of absolute alcohol and is followed immediately by the addition of 175 g (1.06 moles) of ethyl phenylacetate (1). Stirring is discontinued at once, the reaction flask is lowered from the stirrer, and a 2 L beaker is made ready. Within four to six minutes after the ethyl phenylacetate (1) has been added, crystallization sets in. The contents of the flask are transferred immediately to the beaker at the first sign of crystallization, which is nearly instantaneous.
The nearly solid paste of the sodium derivative is allowed to cool to room temperature and then stirred thoroughly with 800 mL of dry ether. The solid is collected by suction and washed repeatedly with dry ether. The phenyloxaloacetic ester (3) is liberated from the sodium salt with dilute sulfuric acid (29 mL of concentrated sulfuric acid in 500 mL of water). The almost colorless oil is separated, and the aqueous layer is extracted with 3 x 100 mL portions of ether, which are combined with the oil. The ethereal solution is dried over anhydrous sodium sulfate (Na2SO4) or anhydrous magnesium sulphate (MgSO4), and the ether is distilled off. The residual oil, contained in a modified Claisen flask having a fractionating side arm with thermometer, is heated under a small pressure of about 15 mm Hg in an oil/sand bath. The temperature of the bath is brought gradually to 175 °C and kept there until the evolution of carbon monoxide is complete (use bubbling vessel to check of gas releasing). During this process, the heating is momentarily discontinued in the event of a temporary increase in pressure. At the end of the reaction (five to six hours) the oil which has distilled is returned to the flask, and the ethyl phenylmalonate (4) is distilled at reduced pressure. The fraction boiling at 158–162 °C/10 mm Hg weighs 189–201 g (80–85 % of the theoretical amount).
Notes
1. A high grade of absolute alcohol is essential. Ordinary "absolute" alcohol may be treated with about 5 % of its weight of Na and distilled directly into the reaction flask.
2. To ensure absolutely dry and neutral reagents, the ethyl oxalate (Org. Syn. Coll. Vol. I, 1941, 261) and ethyl phenylacetate (Org. Syn. Coll. Vol. I, 1941, 270) were shaken with anhydrous potassium carbonate and distilled carefully under reduced pressure, after a preliminary heating under atmospheric pressure until their boiling points were reached.
2. To ensure absolutely dry and neutral reagents, the ethyl oxalate (Org. Syn. Coll. Vol. I, 1941, 261) and ethyl phenylacetate (Org. Syn. Coll. Vol. I, 1941, 270) were shaken with anhydrous potassium carbonate and distilled carefully under reduced pressure, after a preliminary heating under atmospheric pressure until their boiling points were reached.
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