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    Ognian Dimitrov
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    61 views12 pages

    Ephedrine

    Uploaded by

    Ognian Dimitrov

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
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    of 12
    2.0 FEB 2006 ORIGINAL FORM2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See Section 10) AN IMPROVED PROCESS FOR THE RESOLUTION OF dl-EPHEDRINE Malladi Drugs & Pharmaceuticals itd, No::52, Jawaharlal Nehru Road, Ekkattuthangal, Chennai- 600 097, an Indian company registered under the Indian companies act 1956 and Emmetien Biotech Pharmaceuticals Ltd,No:501, Sentinel, Hiranandani Gardens, Powai, Mumbai 400076, an Indian company registered under the indian companies act 1956. The following specification particularly describes the nature of this invention and the manner in which it is to be performed: Field of Invention ‘The invention relates to an improved process for the resolution of dl Ephedrine to prepare L-Ephedrine The l-Ephedrine prepared by the process of the present invention is a very well known sympathomimetic agent widely used in cough & cold preparations. Sympathomimetic agents are in use in medicine since long, for their effects on the blood vessels and the peripheral and central nervous system The present invention relates to one such sympathomimetic agent “I-Ephedrine™ Background of Invention: |- Ephedrine is currently produced via a microbial biotransformation process using different species of yeasts with Benzaldehyde as the aromatic substrate. The process involves the condensation of an active acetaldehyde (which is generated from Pyruvicacid produced by yeast) and Benzaldehyde giving rise to L-Phenyl Acetyl Carbinol(PAC), This PAC on catalytic hydrogenation in the presence of methylamine yields I-Ephedrine(u s patl 956950 ,c a.28,4072) Reduction of L.-Phenyl acetyl carbinol using Sodiumborohydride was mentioned in the patent CZECH.98260,1961 In czech 186,027, Platinum catalyst was used for the reduction Patent no- 302,940 (France) describes a method for the preparation of Ephedrine (synthetic) from Propiophenone by brominating the Propiophenone condensing with methylamine and on reducing the obtained Ephedrone. But this route gives only racemic form of Ephedrine ie dl-Ephedrine. To obtain I-Ephedrine this racemic form needs to be resolved RACEMIC means mixture of 50%d-isomer and S0%l-isomer with optical activity of zer0 RESOLUTION is the method of resolving racemic mixture into optically active components (d-isomer and |-isomer) involves use of appropriate resolving agent(s) There are many methods to resolve this racemic form. In the conventional resolution of dl-base an expensive resolving agent generally required is one equivalent to that of dl-base to form a mixture of salts of diastereomers as shown below. Conventional resolution: 1, di-Base (1 mole)+ d- Acid (1eq) ~ d-Base d-Acid + Mother liquor() (resolving agent) (diastereomer) 2. Mother liquor-— I-Base.d-acid (diastereomer) -d-hydrochloride salt+ Mother liquor (2)(d-acid) 3. d-Base d-Acid 4, leBase d-Acid ~ ~-I-hydrochloride salt Mother liquor(3)(d-acid) 5. Mother liquor (2)}+Mother liquor(3)- acid ‘One mole of Racemic base (dl-base) consisting of 0.5 moles of d-base isomer and 0.5 moles of ¢ isomer needs | mole of resolving agent(d-acid) to form diastereomeric salts d-base d-acid (0.Smole:0.Smole) and I-based-acid (0,Smole:0.Smole),These salts vary widely in properties mainly in their solubilities in organic solvents . When the salt (dbase-d acid) precipitates out due to its solubility difference and the other (I-base-d acid) remains in reaction is performed in suitable solvent one diastereomeric solution (mother liquor) as shown in step-1. This salt (I-base-d acid) is precipitated by cooling the mother liquor -step-2. From the isolated salt ( namely from steps 2) the required isomer i.e in this case, the I-isomer is isolated, as hydrochloride salt, by treating with hydrochloric acid (step-4). Similarly, d-isomer contained in the salt (dbase-d acid) 0.0obtained in step (i) is also isolated by treating with hydrochloric acid . (step-3). As the resolving agent, namely (d acid) is involved in the salt formation with both the salts( in steps (i) & Step (ii) , it has to be recovered by mixing both the mother liquors obtained from steps 3 &4 by further processing (step-5) To summarise , in the conventional resolution process , one requires 1 equivalent of resolving agent and its recovery involves 5 steps leading to more handling loses of the resolving agent_and time, Thus the conventional resolving process to obtain the L isomer is a time consuming , tedious and is not applicable industrially Resolution of dl-Ephedrine is described in Resolution of organic compounds, page no180 by using d-mandelic acid, But the diastereomer complex obtained needs to be purified many times before converting in to the required salt Mandelate salts of Ephedrine were also studied in J. ORG.CHEM 8,564-71(1943) Resolution of dl-ephedrone (penultimate step product of dl-Ephedrine) with Dibenzoyl tartarie acid is described in “Resolution of organic compounds” page 167 , Handling of Another process for the preparation of I-Ephedrine has been described in chemical abstracts vol :50 page 868 by converting I-(+)Pseudo Ephedrine using acetic anhydride to form I+)n- acetyl pseudo Ephedrine and reacting with thionyl chloride and hydrolyzing further to give I-Ephedrine CA: vol: 86: 29451) ,1977 describes a process for the preparation of I-Ephedrine from pseudo Ephedrine by oxidizing and stereospecific reduction CA:86, VOL: 1977:121598K Resolution of dl-Ephedrine using d-trans-2-benzamidocyclohexane carboxylic acid or I cis 2-benzamidocyclohexane carboxylic acidwith 46,8%and 70.9% yields of I-Ephedrine hel CA:VOL:86:171704:1977 CZECH. 165624 describes a method to separate I-Ephedrine salt from mixture of I-Ephedrine and dl-Ephedrine. By dissolving the in aqueous sodium hydroxide and extracting with butyl acetate which on further concentration and cooling, yielded crystals of dl-Ephedrine base and mother liquor yielded I-Ephedrine base US patent no 3478101(nov1 1,1969) describes a process for the preparation of optically active bases by reacting the recemic base with optically active half amides of unsaturated aliphatic dicarboxylic acids. This process of preparation of half amides involving use of unwanted isomer of the molecule to be resolved is very combursome and making the isolation of pure required isomer more difficult US patent no 4656303(1987) has described a method for the resolution of racemic mixture in to optically active isomers using a resolving agent and optically inactive agent in a solvent, the objective was not to make I-Ephedrine but to use LEphedrine as resolving agent In US patent no 6015903,resolution of di-Ephedrine is carried out with 4-24- dichlorophenoxy propionic acid but yields reported is only 40% US patent no 6235927 the e process involves the separation of mixtures of enantiomers in which more than one resolving agents is used, of which at least one resolving agent is optically active and which yields a diastereomer complex containing at least two resolving agent in optically active form .In this invention also Ephedrine is used as one of the resolving agent . US patent no 3478101,(1969) describes a process for resolving dl-Ephedrine into its optically active components by using d-Arabinose as the resolving agent .They followed the conventional method of resolution for resolving using 1eq of resolving agent but could not achieve high yields ( <80%) when tried with less than leq Resolving agents used in the literature for the purpose of resolving dl-Ephedrine include J-monomentholester of succinic acid (US patent no 2240319), d-alpha-[4-arsono- anilino]-propionamide(bulletin de la societechimique de france[4]vol .43,p.1254- 1256)and d-tartaric acid. |-Monomentholester of succinic acid is prepared by partially esterifying optically inactive succinic acid with natural I-mentholwhich is optically active but chemically neutral so as to impart optical activity to succinic acid while preserving its acidity. Due to the presence of ester bonds this material is unstable in the treatment after resolution and also I- menthol is a very expensive material d-alpha-[4-arsono-anilino]-propionamide is not a commercially available material.it can be synthesized in racemic form which needs to be resolved using other resolving agents which is tedious While persuing the literature on resolution of dl-Ephedrine by d-tartaric acid Journal of Pharmaceutical Society of Japan (vol47,1927,p109) mentions |-Ephedrine ~d-bitartarate crystallizes out first from the solution . However the German patent no 549970 states d- Ephedrine -

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