Title of Invention

AN IMPROVED PROCESS FOR THE RESOLUTION OF DL-EPHEDRINE

Abstract

The invention disclosed in this application relates to an improved process for resolving dl-Ephedrine . The process results in the preparation of the two isomers d- ephedrine & l-Ephedrine . The process involves using enantiostoichiometric quantities of a resolving agent and an achiral acid where in one enantiomer forms selectively diastereomer complex with the resolving agent and the other isomer forms salt with the achiral acid facilitating isolation of I -ephedrine. The 1-Ephedrine prepared by the process of the present invention is a very well known sympathomimetic agent widely used in cough &cold preparations.

Full Text

Field of Invention The invention relates to an improved process for the resolution of dl Ephedrine to prepare 1-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 "l-Ephedrine" Background of Invention: 1- 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 1-Ephedrine(u.s.patl956950 ,c.a.28,4072).Reduction of L-Phenyl acetyl carbinol using Sodiumborohydride was mentioned in the patent CZECH.98260,196 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 i.e dl-Ephedrine. To obtain l-Ephedrine this racemic form needs to be resolved. RACEMIC means mixture of 50%d-isomer and 50%1-isomer with optical activity of zero. RESOLUTION is the method of resolving racemic mixture into optically active components (d-isomer and 1-isomer) involves use of appropriate resolving agent(s). 2 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. dl-Base (1 mole)+ d- Acid (leq) d-Base d-Acid + Mother liquor(l) (resolving agent) (diastereomer) 2. Mother liquor 1-Base.d-acid (diastereomer) 3. d-Base d-Acid d-hydrochloride salt+ Mother liquor (2)(d-acid) 4,1-Base d-Acid 1-hydrochloride salt+ Mother liquor(3)(d-acid) 5. Mother liquor (2)+Mother liquor(3) d-acid One mole of Racemic base (dl-base) consisting of 0.5 moles of d-base isomer and 0.5 moles of 1-base isomer needs 1 mole of resolving agent(d-acid) to form diastereomeric salts d-base d-acid (0.5mole:0.5mole) and 1-based-acid (0.5mole:0.5mole).These salts vary widely in properties mainly in their solubilities in organic solvents . When the reaction is performed in suitable solvent one diastereomeric salt (dbase-d acid) precipitates out due to its solubility difference and the other (1-base-d acid) remains in solution (mother liquor) as shown in step-1. This salt (1-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 1-isomer is isolated, as hydrochloride salt, by treating with hydrochloric acid (step-4). Similarly, d-isomer contained in the salt (dbase-d acid) O.Oobtained 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). 3 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 nol80 by using d-rnandelic 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 DibenzoyI tartaric acid is described in "Resolution of organic compounds" ,page 167 , Handling of dl-Ephedrone is difficult as it decomposes very fast in basic media giving rise to dark coloured unknown impurities. Another process for the preparation of 1-Ephedrine has been described in chemical abstracts vol .50 page 868 by converting l-(+)Pseudo Ephedrine using acetic anhydride to form l-(+)n- acetyl pseudo Ephedrine and reacting with thionyl chloride and hydrolyzing further to give 1-Ephedrine CA: vol. 86: 29451] ,1977 describes a process for the preparation of 1-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 1-cis 2-benzamidocyclohexane carboxylic acidwith 46.8%and 70.9% yields of 1-Ephedrine hcl. CA:VOL:86:171704:1977 CZECH.165624 ,describes a method to separate 1-Ephedrine salt from mixture of 1-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 1-Ephedrine base. 4 us patent no 3478101(novl 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 1-Ephedrine but to use l-Ephedrine as resolving agent. In US patent no 6015903,resolution of dl-Ephedrine is carried out with d-2,4-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 1 eq of resolving agent but could not achieve high yields ( Resolving agents used in the literature for the purpose of resolving dl-Ephedrine include 1-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-I256)and d-tartaric acid. 5 1-Monomentholester of succinic acid is prepared by partially esterifying optically inactive succinic acid with natural 1-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 1-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,pl09) mentions 1-Ephedrine -d-bitartarate crystallizes out first from the solution . However the German patent no 549970 states d-Ephedrine -d-bitartrate crystallizes first and is shown to be more difficultly soluble one. Further the Journal of the American Chemical Society vol. 51p. 1906-1909 indicates that while d-tartaric acid readily forms crystalline salts with dl-Ephedrine , it is incapable of resolving said Ephedrine thus denying the possibility of dl-Ephedrine being resolved by d-tartaric acid. These experimental procedures were repeated in US patent no 3478101 and disclosed that the resolution of dl-Ephedrine with d-tartaric acid as resolving agent could reasonably be deemed substantially impracticable from the industrial point of view. The problem with the resolution of d-tartaric acid is that the diastereomers produced will have only slightly different solubilities in the solvents, thus resulting in precipitation of mixtures giving rise to low optical purity. In US patent no 5962737, a process has been described by the phase transfer resolution of racemic mixtures of 2-amino-l-phenylpropanol and its derivatives into their optically pure isomers by reacting a racemic mixture with the mono alkali metal salt of tartaric acid ester in a two phase system of a hydrocarbon and water. The resolving agent used 6 was 0.5 eq and the recovery and the recycling of the resolving agent was not discussed which is very crucial for any resolution process. In the method , according to the present invention optically active acid is used along with an achiral acid (achiral acid is one which is not optically active , in other words such an acid does not have a chiral center ) . Such an achiral acid is easily available at low cost and the resolution employing such an acid in combination with the resolving agent results in isolation of the desired isomer in high purity ( 99 % ) and yield(83.5% as 1st crop) In a preferred embodiment of the present invention , by the combination of the resolving agent and the achiral acid , the amount of the resolving agent required is only stoichiometric Specifically , in dl-Ephedrine base resolution , according to the present invention ,d-isomer is converted to a saU of optically active acid and 1-isomer forms salt with an achiral acid as shown below. I.dl-Base(lmole) + d- Acid*{0.25eq) + Achiralacid(0.5eq) — d-Base d-Acid-t- mother liquor(l) 2.Mother liquor( 1) I-hydrochloridesaU 3.d-Base d-Acid d-hydrochloridesalt+ Mother liquor (2)(d-acid) 4. Mother liquor (2) d-acid These two salts namely , d-base-d-acid and 1-base acid , produces in step (i)) differ in solubility in organic solvents . So when the mixture is cooled under stirring d-Base-d-Acid typically being less soluble precipitates out of the solution first, while 1-Base acid remains in solution. The required 1-lsomer is isolated as hydrochloride salt by further acidifying and concentrating the solution. 7 Thus , in the present invention , the required 1-isomer can be isolated in purest 99% form in two steps (stepsl&2 ), compared to 3-step process in the conventional resolution . The requirement of resolving agent acid is very less i.e 0.25 eq (stochiometric ) , In addition it is also possible to recover a major amount of the resolving agent in three steps (steps-1,2,&3 ) as against 5 step process in conventional process. Consequently the process becomes economical Therefore the method of the present invention is quite preferable for resolution of racemic Ephedrine as an industrial procedure. Objectives of Invention The main objective of the present invention is to provide an improved process for the resolution of dl Ephedrine Another object of the present invention is to provide an improved process for the preparation of d-Ephedrine & 1-Ephedrine by resolving the dl-Ephedrine using enantiostoichiometric ratio of resolving agent. Another objective of the present invention is to provide an improved process for the preparation of i-Ephedrine by resolving the dl-Ephedrine involving the use of an enantio stoichiometric quantity of resolving agent in combination with an achiral acid. Still another objective of the present invention is to provide an improved process for the preparation of 1-Ephedrine by resolving the dl-Ephedrine with reduced process steps for isolating 1-Ephedrine hydrochloride (99%pure) Yet another objective of the present invention is to provide an improved process for for the preparation of 1-Ephedrine by resolving the dl-Ephedrine involving the recovery of derivative of tartaric acid from the mother liquors with highest yield. 8 As a result the present invention provides a simple but efficient, less time consuming ,less tedious method for resolving the optical isomeric forms of dl-Ephedrine and there fore provides at a lower cost. Description of invention: Accordingly the present invention provides an improved process for the preparation of 1-Ephedrine from dl Ephedrine which comprises (i).dissolving dl-Ephedrine base in an organic solvent (ii) adding an achiral acid to the resulting solution and stirring the solution for a period ranging from 5 min to 3hrs (iii) adding a solution of an ester of tartaric acid in an organic solvent to the solution obtained in step ( ii) at a temperature in the range from-10°C to 70° C for a period ranging from 5 min to 5hrs (iv) stirring the resulting solution for a period ranging from l0min to 10 hr (v) adding a polar solvent to the resulting solution in step (iv) and cooling to a temperature in the range of-10°C to 40°C to obtain a slurry containing solid mass of d-Ephedrine -tartaric acid ester complex (vi) maintaining the resulting slurry for a period ranging from 15min to 10 hr and filtering to obtain a mother liquor (vii) .adding to the mother liquor , concentrated or dil hydrochloric acid and concentrating the mother liquor ,. 9 (viii) adding water or solvents to the concentrated mother liquor. (ix) cooling the concentrated mother liquor to a temperature in the range of -15°C to 40°C and filtering to get 1-Ephedrine hydrochloride. (x) adding organic solvent along with organic or inorganic acids to the d-Ephedrine -tartaric acid ester complex contained in the residue in step ( vi) and removing water present in the acid used by known methods (xi) adding an organic solvent to the concentrated mass obtained in step ( x) under stirring for a period ranging from lOmin to lOhr and filtering , the d-Ephedrine hydrochloride remaining as the residue and the mother liquor containing the resolving agent and (xii) concentrating the mother liquor obtained in step (xi) and basifying and acidifying by conventional methods and filtering the resolving agent. The Ephedrine base used in step-(i) may be selected fi-om derivatives of 2-amino -1 -phenyl propanol derivatives . The solvent used in the step ( I ) may be selected fi-om organic solvents or water. The acid used in step -(ii) may be preferably acetic acid. Conventional Esters of tartaric acid used in step-(iii) may include dibenzoyl tartaric acid and ditoluoyl tartaric acid , the preferred one being dibenzoyl tartaric acid of 0.2 to 1.0 eq to that of base , preferably , 0.25eq in solvent, preferably methanol at a temp ranging from , preferably 30-35°, for a period preferably ranging from lOmin.to 30 min .Stirring of the solution in step (iv) is carried out for preferably 30to 60 min The polar solvents added in step (v) may be preferably water and the amount may be in the range fi-om 2to 10 times to the quantity of the base , preferably 3.5 times , and the cooling is done to a temperature in the range , preferably 20° C to 40 deg C 10 The resulting mass is maintained in step-(vi) preferably for 1hr before filtering the Ephedrine- tartaric acid ester complex. The resulting mass is concentrated in step (vii) after the addition of concentrated or dil hydrochloric acid . The solvent used in step-(viii) may be selected from water, aliphatic ketones or alcohols , the preferred one being acetone The mass obtained is cooled in step-(ix) to a temperature in the range , preferably 10°C to 15° C before filtering the 1-Ephedrine hydrochloride. hi step-(x) the solvents like aliphatic ketones or aromatic ketones or alcohols preferably benzene are added to Ephedrine-tartaricacidester complex along vsath organic or inorganic acids , preferably hydrochloric acid and heated to evaporate solvent. Solvents like aliphatic ketones or aromatic ketone or alcoholspreferably acetone is added under stirring for preferably 15 min to 30 min while filtering the d-Ephedrine salt. The mother liquor of step (xi) is concentrated and basified by adding water and acidified and filtered the ester of tartaric acid The details of the invention are given in the examples given below which are provided solely to illustrate the invention and therefore should not be construed to limit the scope of the invention . Example 1 dl-Ephedrine base : 200 g d-Dibenzoyltartaric acid : 125.45 g Methanol :261ml Dissolved dl-Ephedrine base 200gm (1.21 mole) in 261 ml of methanol at room temperature followed by acetic acid 40.38g(0.67mol). Stirred for 10 mimutes. 11 d-Dibenzoyltartaric acid 125.45g (0.33mole) was dissolved in 170 ml of methanol and was added at 30 - 35°C during period of 10 minutes. The resulting mass is stirred for 30 -minutes 703 ml water is added and cooled to 20°C and maintained for 1 hr. The material precipitated out was filtered to obtain d-Ephedrine -dibenzoyi tartarate 198 g melting at 175-177°C . Specific rotation was - 49.0° (5%in methanol). To the mother liquor was added with 103 ml cone, hydrochloric acid and evaporated to dryness. On addition of 300 ml of acetone to the residue and on cooling to 10 °C and filtration yielded 101 g of 1-Ephedrine hydrochloride. Melting point 215-218°C , Specific rotation -33.5°. The mother liquor was concentrated and on cooling another 4 g of 1-Ephedrine hydrochloride (2ndcrop) was isolated which was mehing at 200-202°C and showing optical rotation of-26.6°. To 198 g of d-Ephedrine dibenzoyi tartrate,570 ml of benzene and 48 ml of 35 % hydrochloric acid were added and benzene was evaporated and 200 ml of acetone was added stirred for 15 minutes and fdtered Which yielded 99 g of d- Ephedrine hydrochloride melted at 220 -221°C showing optical rotation of + 35.2°. Acetone mother liquor basified and acidified to recover dibenzoyi tartaric acid in 90 % yield showing optical rotation of-113° and melting point 88-93°C. • Advantages of the invention 1. The process uses very small quantities of resolving agent which is easily available 2. The resolving agent used can be recovered almost to the theoretical yield. 3. Resolution process is simple as it requires lesser number of steps and the L-Ephedrine is obtained in 99 % purity and 83.5%yield (as 1st crop). 4. The process is very economical and useful for commercial production and there fore provides at very low cost. 12 1. An improved process for the preparation of 1-Ephedrine &d-Ephedrine from dl-Ephedrine which comprises (i).dissolving dl-Ephedrine base in an organic solvent as mentioned here under, (ii) adding an achiral acid as mentioned here under, to the resulting solution and stirring the solution for a period ranging from 5 min to 3hrs (iii) adding a solution of an ester of tartaric acid in an organic solvent to the solution obtained in step (ii) at a temperature in the range from 10OC to 70° C for a period ranging from 5 min to 5hrs (iv) stirring the resulting solution for a period ranging from lOmin to 10 hr (v) adding a polar solvent to the resulting solution in step (iv) and cooling to a temperature in tiie range of-10°C to 40°C to obtain a slurry containing solid mass of d-Ephedrine -tartaric acid ester complex (vi) maintaining the resulting slurry for a period ranging from 15min to 10 hr and filtering to obtain a mother liquor ,separating d-ephedrine (vii) adding to the mother liquor, concentrated or dil hydrochloric acid and concentrating the mother liquor,. (viii) adding water or solvents to the concentrated mother liquor . (ix) cooling the concentrated mother liquor to a temperature in the range of -15°C to 40°C and filtering to get 1-Ephedrine hydrochloride. (x) adding organic solvent along with organic or inorganic acids to the d-Ephedrine -tartaric acid ester complex contained in the residue in step ( vi) and removing water present in the acid used by known methods (xi) adding an organic solvent to the concentrated mass obtained in step ( x) under stirring for a period ranging from l0min to l0hr and filtering, the d-Ephedrine hydrochloride remaining as the residue and the mother liquor containing the resolving agent and (xii) concentrating the mother liquor obtained in step (xi) and basifying and acidifying by conventional methods and filtering the resolving agent. 2. The improved process as claimed in claiml wherein the Ephedrine base used in step-(i) is selected fix)m derivatives of 2-amino -1-phenyl propanol. 3. The improved process as claimed in claims 1 to 2 wherein the organic solvent used in step (I) is selected from organic solvents or water, preferred is methanol. ,y^ 4.The improved process as claimed in claims 1 to 3 wherein the achiral acid used in step -(ii) is acetic acid ,/ 5. The improved process as claimed in claims 1 to 4 wherein the tartaric acid ester used in step-(iii) is selected from dibenzoyi tartaric acid and ditoluoyl tartaric acid, preferably dibenzoyl tartaric acid / 6. The improved process as claimed in claims 1 to 5 wherein the amount of ester used is 0.2 to 1.0 eq to that of the base used , preferably 0.25eq . 7. The improved process as claimed in claims 1 to 6 wherein the solvent used to dissolve the tartaric ester is methanol 14 8. The improved process as claimed in claims 1 to 7 wherein the step (iii) is effected at a temp ranging from 30-35° C for a period ranging from a period 1 Omin to30 min 9. The improved process as claimed in claims 1 to 8 wherein the stirring the solution is done in step (iv) for a period ranging 30 min to60min 10. The improved process as claimed in claims 1 to 9 wherein the polar solvents used in step (v) is water and the amount used is in the range from 2to 10 times to the quantity of base used preferably 3.5 times 11. The improved process as claimed in claims 1 to 10 wherein the cooling in step (v) is effected in the range preferably 20° C to 40 deg C 12. The improved process as claimed in claims 1 to 11 wherein the mass obtained in step (vi) is maintained for Ihr before filtering the Ephedrine - tartaric acid ester complex. " -^ 13. The improved process as claimed in claims 1 to 12 wherein the mass is concentrated in step(vii) after the addition of concentrated or dil hydrochloric acid . 14. The improved process as claimed in claims 1 to 13 wherein the solvent used in step-(viii) is selected from water, aliphatic ketones or alcohols , preferably acetone 15. The improved process as claimed in claims 1 to 14 wherein the mass is cooled in step-(ix) to a temperature in the range of 10°C to 15°C before filtering the material. 16. The improved process as claimed in claims 1 to 15 wherein the solvents used in step-(x) is selected from aliphatic ketones or aromatic ketones or alcohols preferably benzene or toluene , . , ti hydrochloric acid 15

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