CHAPTER-II a Novel Process for Synthesis of Eprazinone Hydrochloride Which Is a Drug from the Class of Antitussive Agents
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CHAPTER-II A novel process for synthesis of Eprazinone hydrochloride which is a drug from the class of antitussive agents. INTRODUCTION : Antitussive drugs are widely used in the treatment of coughs. They are particularly indicated in nonproductive cough, usually associated with different respiratory diseases varying from mild throat infections to the more serious bronchitis and asthma. Nonproductive cough is often painful and fatiguing to the patient especially during the night when, lying down, relief from this persistent reflex is greatly desired. The main ways used to inhibit the cough reflex involve either suppressing the cough center or anesthetizing the respiratory mucosa. Several drugs are available for the treatment of cough, but the number of safe and effective antitussive agents devoid of central effects or local anesthetic activity is rather limited. Opioid alkaloids still seem to be the most effective compounds available, in spite of their several well-established side effects and the risk of addiction. Morphine is an effective antitussive at doses lower than the doses that produce analgesia and sedation. It is not commonly used for antitussive activity due to side effects and the potential for abuse and addiction. Morphine has poor oral bioavailability due to a significant first-pass effect by the liver. Codeine, the 3-methoxy derivative of (-)-morphine, is the most notable representative of the morphine family, and its major side effects, such as sedation, depression, and constipation, are well known.1 Methylation of morphine significantly improves the oral bioavailability by reducing the first-pass effect. Codeine phosphate and codeine sulfate are found in many preparations, including tablets, liquids, and syrups. Codeine has analgesic effects that are about one-tenth that of morphine, but its antitussive potency is about equal to that of morphine. The side effects of codeine are significantly less than those seen with morphine at antitussive doses. Toxicity (especially in cats) is exhibited as excitement, muscular spasms, convulsions, respiratory depression, sedation, and constipation. Codeine should not be used after GI tract surgery. The potential for addiction and abuse of codeine is considerably lower than that for morphine. 64 H CH3 CH N N 3 H H HO MeO O O H OH OH Morphine Codeine The antitussive effect does not appear to be related to the binding of traditional opiate receptors. For example, dextromethorphan is an opiate derivative with good antitussive activity, but it does not have activity at opiate receptors and is not analgesic or addictive. For many years, novel antitussives have been sought through structures incorporating the essential features of codeine series.2 Dextromethorphan and dimemorphan , which have the same absolute configuration as (+)-morphine, emerged as clinically useful antitussives with fewer side effects than codeine, although they both showed potent central activity.3 Dextromethorphan is technically not considered an opiate because it does not bind to traditional opiate receptors and is not addictive or analgesic. It is the D-isomer of levorphanol. The L-isomer of levorphanol has addictive and analgesic properties. Dextromethorphan is the safest antitussive to use in cats and is reported to be more efficacious in cats than codeine. In addition, dimemorphan has been reported to have analgesic properties 4. H CH H CH N 3 N 3 H H MeO H3C Dextromethorphan Dimemorphan Further simplifications of the morphine nucleus provided newer antitussive agents, structural families less closely related to the morphinans. One of the most crowded class is 65 represented by the phenothiazines among which pipazetate 5 was shown to exhibit antitussive properties, through a central mechanism of action, together with antibronchospastic effects. Clophedianol6 and cloperastine 7 belong to another big class of antitussives which are bis- arylmethane/ethane derivatives provided with lateral chains containing tertiary amines. The former is reported to depress the cough center and stimulate the respiratory center. Besides, it shows antibronchospastic properties. More selectively, cloperastine does not interact with the respiratory center. O Cl CH3 O O N N CH3 N N OH S Pipazetate Clophedianol Cl O N Cloperastine In the group of 1,4-disubstituted-piperazines; eprazinone, zipeprol 8 and dropropizine 9 are the best known representatives. Zipeprol is a centrally acting cough suppressant which acts as a local anaesthetic and may also have mucolytic, antihistamine-like and anticholinergic properties. 10 It is sold with several brand names such as Zinolta and Respilene. It is not available in the United States or Canada and has been discontinued in Europe. It is still available in some countries in Asia and South America. 66 Zipeprol has been used recreationally and is heavily abused in Korea, mainly for the hallucinations it produces. Such abuse has become an issue due to the seizures and various neurological side effects it causes at high dosages. Many fatalities have been reported. 11 Dropropizine is a racemic non-opiate antitussive agent which has been used clinically for many years. More recently, Levodropropizine the levo-rotatory (S)-enantiomer of dropropizine 12 showed less sedative properties than the racemate or the dextro isomer, maintaining a considerable analgesic activity. Compared with the racemic drug, levodropropizine exhibits in animal models similar antitussive activity but considerably lower central nervous system (CNS) depressant effects. It is also less likely to cause sedation in treated patients. CH3 N OH N NO N OCH 3 O CH3 OCH 3 Eprazinone Ziperol OH N N OH Dropropizine In the class of heterocyclic oxadiazoles, oxolamine 13 emerged as one of the most active representatives. This antitussive agent was suggested to have a predominantly peripheral mechanism of action because of its major activity in tests involving a diffuse stimulation of the bronchial tree. 67 CH3 H C 3 N N O N Oxolamine 68 PRESENT WORK Eprazinone hydrochloride is an antitussive drug that affects the dissolution of mucus in the respiratory tract. Due to its broncho-secretolytic activity, the drug is used in ailments of respiratory tract and the main active ingredient in several expectorant formulations. Eprazinone, chemically represented by 3-[4-(2-ethoxy-2-phenyl-ethyl) piperazin-1-yl]-2- methyl-1-phenyl-propan-1-one possesses mucolytic and antitussive activity and administered in the form of its hydrochloride salt. CH3 N NO O CH3 Eprazinone There are mainly three synthetic routes available in literature for industrial synthesis of eprazinone which involves Mannich reaction of piperazine moiety and propiophenone in presence of paraformaldehyde/trioxymethylene. One of the literature method for preparation of eprazinone ( 1) as described in scheme- 114 involves reaction of 2-phenyl-2-ethoxy ethyl bromide (6) with excess of anhydrous piperazine to give 1-(2-ethoxy, 2-phenyl)ethyl piperazine (7). Hydrochloride salt of intermidiate-7 on Mannich reaction with propiophenone, trioxymethylene and hydrochloric acid in ethanol gave eprazinone hydrochloride with an overall yield of 30%. The intermediate 2-phenyl 2-ethoxy ethyl bromide (6) has been prepared by the reaction of styrene, ethanol and tert-butylhypobromite. 69 H CH 3 N CH3 O O NH N CH Br N 2 t-Butyl hypobromite H + H3C OH MDC Ethanol/reflux Styrene 6 7 O CH3 CH3 N NO Trioxymethylene EtOH/HCl O . 2HCl CH Reflux 3 Eprazinone hydrochloride (1) Scheme 1 In another synthesis 15 of Eprazinone ( 1) as described in scheme 2, mono CBZ-protected piperazine (8) on Mannich reaction with propiophenone, paraformaldehyde in presence of hydrochloric acid in ethanol gives intermediate 9 which on subsequent CBZ-deprotection followed by N-alkylation with 2-phenyl-2-ethoxyethyl bromide (6) provides the desired target molecule, eprazinone. O Paraformaldehyde O H N EtOH/HCl CH3 Reflux CH3 N O N + N CBZ O Propiophenone 8 9 CH3 O Br CH N Deprotection CH3 NH 3 N NO O O CH3 10 Eprazinone Scheme 2 70 In yet another approach for the synthesis of eprazinone,16 Grignard reagent of propyl 3-[4-(2-ethoxy-2-phenyl-ethyl) piperazin-1-yl]-2-bromide was reacted with benzonitrile, in diethyl ether. Subsequent hydrolysis with hydrochloric acid yields eprazinone hydrochloride (scheme-3). CN CH3 N Diethylether CH3 N NO + BrMg Hydrolysis N O CH3 O CH3 Benzonitrile 11 Eprazinone Scheme 3 There are many drawbacks associated with these literature processes for industrial production of eprazinone: 1) For preparation of key intermediate 6 (scheme 1), tert-butylhypobromite was used which is hazardous and highly flammable. 2) The preparation of Grignard reagent and its further reaction (scheme 3) requires stringent conditions as they are highly sensitive to moisture, thereby requiring an anhydrous environment. Further, the use of highly inflammable solvent such as diethyl ether makes the process unsuitable for commercial purpose. To overcome these problems, we realized the need to develop an alternative, cost effective and safe process for commercial synthesis of eprazinone. Accordingly, a synthetic study was undertaken to develop a safe and economically efficient process for the synthesis of eprazinone. Scheme 4 describes the retrosynthetic analysis of eprazinone. 71 CH3 ON O NH N O N CH3 CH3 .2 HCl Eprazinone hydrochloride (1) O NH OH NH N N H N O O N Br H CH3 Phenacyl bromide Acetophenone Scheme 4 As per proposed synthetic approach, acetophenone can be easily brominated to give phenacyl bromide which on condensation