Interrogation de Seconde Licence 1998-1999

Synthesis of a Sedative-Hypnotic Drug: Phenobarbital

Introduction

Barbiturates are central nervous system depressants used as hypnotic drugs and anesthetics. They all derive from barbituric acid which was first synthesized in 1864 by Adolph von Baeyer but lacked any sedative properties. At the turn of the century, Emil Fischer synthesized barbital, the first sleep-inducing barbiturate, which was put on the market in 1903 under the name Veronal®.
Following the introduction of barbital as a drug, numerous other barbiturates were synthesized and tested. Studies of these derivatives show that the substituent groups at the C5 position of barbituric acid control both the duration and the type of physiological effect that the drug induces in the human body. Two alkyl or aryl substituents on C5 are required in order to achieve any significant activity. Maximum sedation occurs when the alkyl chains contain five or six carbons. Subtle changes in molecular structure also affect action. Thus, amobarbital requires 30 min to take effect and sedation lasts for 5 to 6 h, while pentobarbital takes effect in 15 min but sedation lasts only for 2 or 3 h. Phenobarbital is another common drug which has been widely used in sleeping pills under trade names such as Luminal®, Gardenal®, Somonal®, etc because of its long-lasting sedative effect (up to 10 h). When the alkyl chains are getting larger, the sedative properties decrease and the substances become anticonvulsants used to treat epileptic seizures. If the alkyl groups are too long or are grafted on one of the two nitrogens of barbituric acid, convulsants are produced.

Molecular Structures

During the past decades, barbiturates were commonly administered as mild sedatives, but have since been replaced by other tranquilizers. Prolonged use of barbiturates leads to narcotic addiction. A barbiturate addict, like a heroin addict, suffers withdrawal symptoms when denied access to the drug. An overdose of barbiturates, especially when used in conjunction with the depressant alcohol, induces a deep sleep and nearly always proves fatal.

Reaction Scheme

Experimental

Intermediate A. Sodium amide (21 g) and anhydrous ether (200 mL) were placed in a dry 1 L three-necked, round-bottomed flask fitted with a tall reflux condenser and an addition funnel. Under constant stirring, freshly distilled phenylacetonitrile (59 g) was added dropwise. A vigorous reaction ensued with gas evolution. When all the nitrile had been added, the reaction mixture was refluxed 30 min. After cooling to room temperature, freshly distilled diethyl carbonate (75 g) was added dropwise. Replacement of the ether lost by evaporation was frequently necessary. After all the carbonate had been added, the flask was warmed another 30 min, then it was cooled in an ice bath and treated with dilute hydrochloric acid until the aqueous layer was acidic. The mixture was filtered and the ether layer was separated and dried over calcium chloride. After removal of the ether and fractional distillation, 66 g of intermediate A were obtained, b.p. 140-148 deg.C/7 mm (nearly all at 145 deg.C).

Intermediate B. To 5.8 g of clean sodium wire in anhydrous ether (150 mL), 47 g of intermediate A (0.25 mol) were added dropwise. The reaction mixture was stirred and refluxed overnight. Unreacted sodium was destroyed by adding a little methanol and fresh ether to replace loss. Freshly distilled iodoethane (50 g) was then added dropwise and the stirring and refluxing continued for 4 days. Fresh ether and more halide were added if necessary. The completion of the reaction was monitored by checking the pH of the mixture in the flask. A few drops of 20% sulfuric acid were then added followed by enough water to dissolve the precipitated solid and to cause a separation of the ether layer. The mixture was decanted and the aqueous solution extracted with fresh ether. The combined ether solutions were dried and the ether evaporated. The residue was fractionally distilled to afford 41 g of intermediate B, b.p. 147 deg.C/11 mm.

Intermediate C. Sodium ethylate, prepared from 7 g of sodium wire in 125 mL of absolute ethanol, was placed in a dry 500 mL three-necked, round-bottomed flask fitted with a reflux condenser and an addition funnel. Next, intermediate B (33 g, 0.15 mol) and urea (10 g) were added and the mixture was refluxed 8 h. The alcohol was then distilled off and the residue dissolved in about 400 mL of water. The unreacted intermediate B was removed by extraction of the water solution with ether. The aqueous solution was then acidified with a slight excess of concentrated hydrochloric acid. The white precipitate of intermediate C (12 g) was filtered off, dried, and used as crude product for the next step. If needed, pure intermediate C can be obtained by recrystallization from ethanol, m.p. 264 deg.C.

Phenobarbital. A solution of intermediate C (10 g) in 500 mL of 3 N hydrochloric acid was refluxed for a short time. Upon cooling, phenobarbital separated as a white crystalline solid, usually in a quantitative yield. Recrystallization from hot water yielded a reasonably pure material, m. p. 171 deg.C. A somewhat higher m.p. (175-176 deg.C) can be reached if ethanol is employed for recrystallization but the recovery is considerably less.

Bibliography

1. Nelson, W. L.; Crechter, L. H.; J. Am. Chem. Soc. 1928, 50, 2758-2762.
2. Chamberlain, J. S.; Chap, J. J.; Doyle, J. E.; Spaulding, L. B.; J. Am. Chem. Soc. 1935, 57, 352-354.
3. Miller, J. A.; Neuzil, E. F., Modern Experimental Organic Chemistry, D. C. Heath: Lexington, 1980, 453-462.
4. Vogel, A. I.; Vogel's Textbook of Practical Organic Chemistry, 5th ed., Longman: Harlow, 1989, 1177-1179.
5. Williamson, K. L.; Macroscale and Microscale Organic Experiments, 2nd ed., D. C. Heath: Lexington, 1994, 568-576.

Nom : .............................

Prénom : ..........................

Sart-Tilman, le 14 octobre 1998

Seconde licence en sciences chimiques 1998-1999

Chimie organique

Interrogation de travaux pratiques

Sur base du schéma réactionnel et des modes opératoires ci-joints, répondez de façon brève, claire et précise aux questions suivantes.
Vos réponses doivent se trouver uniquement dans les espaces prévus à cet effet, sur les faces recto des feuilles. Les faces verso peuvent être utilisées comme brouillons.

Thème I. Analyse générale du mode opératoire

1) Comment procéderiez-vous pour préparer de l'éther anhydre à partir d'une bouteille de solvant pour analyse? A quel point est-il essentiel de veiller lors de cette opération? (4 points)

Réponse

2) En traitant le cas concret des appareils utilisés au laboratoire pour les travaux pratiques, décrivez succinctement les principaux éléments des instruments de chromatographie en phase gazeuse (GC) et en phase liquide sous haute pression (HPLC). Mettez en évidence les principales différences entre ces deux techniques en complétant le tableau suivant: (6 points)

Tableau

3) La synthèse des intermédiaires A, B et C requiert un appareillage sec. Quelles précautions élémentaires (non décrites dans les modes opératoires) prendriez-vous pour exclure l'humidité du montage expérimental? (3 points)

Thème II. Synthèse de l'intermédiaire A

4) Proposez un mécanisme pour la transformation du phénylacétonitrile en intermédiaire A. Indiquez clairement sur votre schéma la structure de l'intermédiaire A. (2 points)

Réponse

5) Quel(s) est/sont le(s) gaz formé(s) au cours de la réaction? Proposez un test simple pour vérifier votre hypothèse. (2 points)

6) En cas de reflux prolongé, un produit secondaire de formule brute C₁₇H₁₂N₂O est formé aux côtés de l'intermédiaire A. Quelles pourraient être sa structure et les raisons de sa formation? (3 points)

Réponse

Thème III. Synthèse de l'intermédiaire B

7) Proposez un mécanisme pour la transformation de l'intermédiaire A en B. Indiquez clairement sur votre schéma la structure de l'intermédiaire B. (2 points)

Réponse

8) Comment évolue le pH du milieu au cours de la réaction et quelle devrait être sa valeur au terme? Justifiez brièvement votre réponse. (3 points)

Réponse

9) Quelle est la formule du solide qui précipite au cours de la réaction? (1 point)

10) Proposez une méthode appropriée pour sécher la solution éthérée d'intermédiaire B. (3 points)

Thème IV. Synthèse de l'intermédiaire C

11) Proposez un mécanisme pour la transformation de l'intermédiaire B en C. Indiquez clairement sur votre schéma la structure de l'intermédiaire C. (2 points)

Réponse

12) Proposez une méthode appropriée pour sécher l'intermédiaire C brut. (3 points)

Réponse

Thème V. Synthèse du phénobarbital

13) Proposez un mécanisme pour la transformation de l'intermédiaire C en phénobarbital. (2 points)

Réponse

14) Pourquoi la 2,4,6(1H,3H,5H)-pyrimidinetrione porte-t-elle le nom usuel d'acide barbiturique malgré l'absence de fonction acide carboxylique ou sulfonique dans cette molécule? (2 points)

Réponse

Question subsidiaire.

15) Que signifient les acronymes LCP et VSEPR? Proposez une traduction française de ces deux termes. (2 points)

Réponse

Retour au sommaire des interrogations Retour au sommaire de /licence/