FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)


"AN IMPROVED METHOD FOR DEHYDROXYLATION OF N-BOC PROTECTED PHENYLPROPANOLAMINES"
Emcure Pharmaceuticals Limited., m Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRTBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.


FIELD OF THE INVENTION
The invention relates to an improved method for dehydroxylation of N-tertiary butyioxycarbonyl protected phenylpropanolamines, particularly the dehydroxylation of N-tertiary butyioxycarbonyl protected pseudoephedrine or ephedrine.
BACKGROUND OF THE INVENTION
Prior art methods disclose numerous methods for the preparation of amphetamines and its derivatives from phenylpropanolamine derivatives.
Conventional methods disclose the utilization of hydroiodic acid and phosphorous (Forensic Science International 1990, 48(2), 123-24) or by transformation of the hydroxy group into a good leaving group like a halo derivative as disclosed in Journal of Medicinal Chemistry 1966, 9, 966-67 or an O-acyl derivative as disclosed in US 6,399,828.
The utilization of hydroiodic acid and phosphorous combination for functional group transformation of the hydroxyl group into the methylene group is difficult to commercialize due to the dangerous hazards of developing a phossy jaw associated with the utilization of large amounts of phosphorous. Further, the yields are only in the range of 35-40%, which is quite low due to the formation of associated impurities.
US 6,399,828 discloses methods for removal of the hydroxyl group comprising acylation of the phenylpropanolamine with an suitable acylating agent followed by treatment with either Pd/H2 or HCOONH4 Pd/C. The conversion in this case is only 80-90% with the rest being the 0,N-diacetylated derivative of the starting product. Hence, the product requires further purification for removal of the impurity and obtaining the desired amphetamine derivative with purity conforming to regulatory guidelines. Experimental results showed that the method utilizmg ammonium formate had lower conversion of only 79% even after heating to a temperature between 65-70°C. Further, the said patent also mentions that ammonium formate has got a tendency to catalyze the rearrangement of O-acetylnorephedrine to N-acetylnorephedrine, hence the product obtained by
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ammonium formate method also invariably requires purification for removal of such associated impurities, thereby reducing the overall yield.
A further modification of methods for removal of the hydroxyl group involves protection of the amino group of the phenylpropanolamines without protection of the hydroxyl group.
WO 2006067794 discloses such a method wherein the amino function is protected with groups like formyl, benzoyl and acetyl to form an amide function, which is then treated with a reducing agent such as raney nickel catalyst followed by removal of the protecting group by treatment with dilute hydrochloric acid under reflux conditions.
This method requires about 3.5 times the weight of raney nickel with respect to the starting material, which is quite enormous on a commercial scale. Also, use of such large amounts of raney nickel on a commercial scale is quite hazardous due to the pyrophoric nature of raney nickel. Further, the deprotection of the protecting groups required harsh conditions such as refluxing and takes a very long time at lower temperatures.
The present inventors have therefore developed a method for the dehydroxylation of phenylpropanolamines comprising protection of the amino group with tertiary butoxy carbonyl group (Boc) by employing di-tert-butyl dicarbonate and then carrying out reduction with raney nickel to give the Boc protected amphetamine derivative, which is then deprotected by hydrolysis at ambient temperature with an appropriate acid to give the desired respective salt of methamphetamine or amphetamine depending upon the initial substrate. The yield was quantitative and the purity conformed to regulatory requirements, without the need for any further purification due to the absence of associated impurities.
The important features of the invention are as follows:
i) the amino group was protected with tertiary butoxy carbonyl group (Boc)
which can be easily carried out by a facile reaction in aqueous medium or utilizing an organic solvent. Protection with tertiary butoxy carbonyl group
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leads to a carbamate function, the method for protection as well as deprotection being very facile and convenient for commercial utilization.
ii) reduction for removal of hydroxy group was carried out with only less than half the amount of raney nickel as compared to prior art. which not only gave optimum yields but also made the reaction comparatively much less hazardous and more economical. Further, the associated impurities, which are formed in prior art as with ammonium formate were also not obtained, as a result the reduced product had high purity, substantially free of impurities.
iii) Removal of the Boc protecting group was easily accomplished by stirring with an acid in an organic solvent at room temperature. The yield obtained was quantitative with desired chemical and optical purity.
iv) The product obtained in each step did not require further purification, therefore, in addition to the quantitative yields in each step, the method developed by the present inventors has advantage over prior art when utilized on a commercial scale.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for preparing amphetamine derivatives from phenylpropanolamines devoid of associated impurities and avoiding the use of further purification.
Another object of the present invention is to provide an improved process for preparing amphetamine derivatives from phenylpropanolamines by a simple, efficient, cost-effective, environmentally safe and commercially viable process utilizing tertiary butoxy carbonyl group for protection of the amino function.
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Yet another objective is the utilization of a mild method for easy protection and deprotection of the amino group.


SUMMARY OF TEE INVENTION
An aspect of the invention relates to providing a method for preparation of amphetamine derivatives of high purity comprising reaction of phenylpropanolamines of formula (II) with di-tert-butyl dicarbonate or tertiarybutoxycarbonyl anhydride to obtain compound of formula (III), further treating with a reducing agent in an organic solvent to obtain compound of formula (IV) followed by hydrolysis with an acid in an organic solvent to obtain compound of formula (I).

Scheme I: Method of the present invention for preparation of amphetamine derivatives of formula (I)
A further aspect of the invention relates to providing a method for preparation of amphetamine derivatives of high purity comprising hydrolysis of compound of formula (IV) with an acid in an organic solvent and in anhydrous conditions to obtain compound of formula (I).
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Yet another aspect of the present invention is to provide a simple, efficient, cost-effective improved process for preparing amphetamine derivatives of formula (I) with high yield and purity and which is environmentally safe and commercially viable.


DETAILED DESCRIPTION OF THE INVENTION
The inventors in pursuit of obtaining an amphetamine derivative of formula (I) in high yield and with both high chemical and optical purity had tried out several experiments using several different protecting groups out of which di-tert-buty] dicarbonate produced excellent results in milder reaction conditions.
It was found that use of tertiary butoxycarbonyl anhydride as a amino group protecting agent for preparation of compound of formula (I) is an easier and convenient method for obtaining compound of formula (I) with high purity and in quantitative yield as compared to prior art methods. Further the deprotection of the &oc protecting group is facile without the formation of any associated impurities, thereby yielding the product of formula (I) with quantitative yield and high purity.
The present invention comprises amino group protection of the compound of formula (II) with Boc anhydride in an organic solvent or water to give compound of formula (III) followed by reduction with a reducing agent such as raney nickel to give Boc protected amphetamine derivative of formula (IV), deprotection of the Boc-group with an acid, preferably in anhydrous conditions at a temperature of 0-30 °C in presence or optionally in absence of an organic solvent gave compound of formula (I).
As used herein the term 'amphetamine and related compounds' refers to the derivatives of amphetamine of formula (I), wherein, if R=H (amphetamine), R=CH3 (methamphetamine) and the 'enantiomers'.
As used herein the term 'ephedrine' refers to ephedrine, pseudoephedrine, norephedrine and its addition salts.
A phenylpropanolamine compound such as pseudoepliedrme hydrochloride (Ila) or ephedrine hydrochloride (IIb) or norephedrine (IIc) was added or suspended in an organic solvent or water.
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The organic solvent was selected from the group comprising of chlorinated solvent, alcohols, water etc.
The organic solvent was preferably methylene chloride or isopropanol or water. Water is employed if the corresponding acid addition salt is used as substrate.
The base is either an inorganic or an inorganic base and is selected from the group comprising of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethyl amine at ambient temperature. The base was preferably sodium bicarbonate or triethyl amine.
Di-tert-butyl dicarbonate or Boc anhydride was added to the mixture and the reaction mixture stirred till completion of the reaction.
N-Boc protection was carried at ambient temperature, preferably in the range of 25°C to 30°C.
The reaction mixture was worked up by water washing and concentrating the organic solvent or by extracting the aqueous reaction mixture with an organic solvent such as ethyl acetate and then concentrating under reduced pressure to give the product of formula (III) having high purity (>99%) and with quantitative yield.
It is worth mentioning that the N-Boc protected ephedrine derivative of formula (III) thus obtained did not require any further purification, and was used as such for the next stage.
The N-Boc protected ephedrine of formula (III) thus obtained was reduced to compound of formula (IV) by benzylic deoxygenation using Raney Nickel catalyst in organic solvent at elevated temperature. The organic solvent was preferably an alcohol or an ester.
The compound of formula (III) was added to an alcohol or ester. The alcohol was selected from methanol, ethanol, isopropanol, n-propanol but preferably isopropanol. The ester was preferably ethyl acetate.
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The amount of raney nickel used was between 1.1 times and 1.75 times gram weight per gram weight of the compound of formula (III) but preferably between 1.4 and 1.6 times gram weight per gram weight of the compound of formula (III).
The reaction can also be carried out with 1.0 time gram weight of raney nickel per gram weight of the compound of formula (III) but higher temperatures are required or the reaction is slow at lower temperatures. Further the reaction can be carried out with amount of raney nickel used between 2.5 times and 3.0 times gram weight per gram weight of the compound of formula (HI) wherein the reaction is faster.
The reaction mixture was heated between 65-90°C, preferably between 65°C and 70°C till completion of reaction. The reaction was performed either in a closed autoclave or in a flask. The reaction also can be carried out below 60°C, but the reaction takes a longer time.
The compound of formula (IV) was isolated by filtering the catalyst and concentrating the filtrate to yield the product with 99% HPLC purity, Due to its high purity, the compound of formula (IV) did not require any further purification, and was used as such for the next step.
The compound of formula (IV) was then deprotected in an acidic medium preferably in anhydrous conditions to yield salt of methamphetamine of formula (la) or amphetamine of formula (lb).
The N-Boc protected amphetamine (IVb) or its N-methyl derivative of formula (IVa) was added to an organic solvent.
The solvent was selected from the group comprising of chlorinated solvents, esters, alcohols, ethers but preferably esters or chlorinated solvents. The esters were selected from the group comprising of ethyl acetate, methyl acetate, isopropyl acetate but preferably ethyl acetate.
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The chlorinated solvents were selected from the group comprising of methylene chloride, ethylene dichloride, chloroform etc, but preferably methylene chloride.
An acid was added to the mixture. The acid was either an inorganic acid or organic acid.
The organic acid was selected from trifluoroacetic acid, methanesulfonic acid etc.
The inorganic acid was hydrochloric acid and was introduced in the reaction mixture, preferably in the gaseous form.
The acid was added to solvent containing the Boc-compound at ambient temperature or optionally cooled between 0-5 °C and stirred at same temperature.
The amount of acid added was between 1.0 and 1.5 equivalent per mole of compound of formula (IV) or when an organic acid like trifluoroacetic acid was employed, the organic acid could be used in 1:1 proportion with an organic solvent such as methylene chloride.
The N-Boc protected amphetamine (Illb) or its N-methyl derivative of formula (Ilia) was added to the mixture at ambient temperature or at 0°C and stirred further till completion of reaction.
After completion of the deprotection reaction, amphetamine or its N-methyl derivative was isolated in the form of its corresponding acid addition salt by concentration of the solvent under reduced pressure.
The corresponding acid addition salts of methamphetamine (la) or amphetamine (lb) were obtained in quantitative yields with purity more than 99%.
It is pertinent to mention that the product thus obtained did not require any further purification as the associated impurities were well below limits or were not detectable.
Although, the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that
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numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All patent and non-patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
The invention is further explained with the help of following illustrative examples,
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EXAMPLES:
Example 1: Preparation of N-Boc-(+)-Pseudoephedrine.
(+)-Pseudoephedrine.HCl (375gms, 1.86moies) was added to an aqueous solution of
sodium bicarbonate (343 g, 4.09 moles) in water (1870 ml) at 25°C temperature followed
by addition of di-tert-butyl dicarbonate (446 g, 2.04 moles) and stirred for 6 hours at
25°C. The progress of the reaction was monitored by HPLC. After completion of
reaction, water (560 ml) was added to the reaction mixture, and extracted with ethyl
acetate. The solvent was removed under reduced pressure to yield the product as a white
solid.
Yield: 493 g (quantitative); HPLC purity: 99%.
Example 2: Preparation of N-Boc protected (+)-methamphetamine. Boc-(+)-pseudoephedrine (493 g, 1.86 moles) was added into isopropyl alcohol (1000 ml) into a 10 litre autoclave and stirred to get clear solution. Raney Nickel (740 g) in isopropyl alcohol (1000 ml, as a slurry) was added at 25°C. Reaction mass was heated at 70-75°C and the progress of the reaction was monitored by TLC and HPLC. After completion of the reaction, the catalyst was filtered and the product was isolated by evaporation of isopropyl alcohol from the filtrate under reduced pressure. Yield: 463 g (quantitative); HPLC purity: 99%.
Example 3: Preparation of (+)-Methamphetamine hydrochloride
N-Boc protected (+)-methamphetamine (463 gms) was dissolved in ethyl acetate (1400ml) at 0°C, was added ethyl acetate (1600 ml) containing 10% of dissolved hydrochloric acid. The reaction mass was stirred and the temperature was gradually raised to 25°C and the stirring was continued for 20 hours. The progress was monitored by TLC, after disappearance of the Boc-protected compound, the volatiles were removed at reduced pressure and the residue was slurred in toluene (1000 ml) at ambient temperature. The product was filtered and dried under vacuum at 50°C to provide the product as a white solid in almost quantitative yield. Yield: 330-340 g; Chiral purity: 99.5%; HPLC purity: 99%.
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Example 4: Preparation of N-Boc-(-)-norephedrine.
(-)-Norephedrine (20 g, 0.132 moles) was added to an aqueous solution of sodium bicarbonate (12.2 g, 0.145 moles) in water (100 ml) at 25°C temperature followed by addition of di-tert-butyl dicarbonate (31.75 g, 0.145 moles) and stirred for 6 hours at 25°C. The progress of the reaction was monitored by HPLC. After completion of reaction, water (40 ml) was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to yield the product. Yield: 33.2 g (quantitative); HPLC purity: 99%.
Example 5: Preparation of N-Boc-protected (+)-amphetamine.
Boc-(-)-Norephedrine (33 g, 0.131 moles) was added into isopropyl alcohol (60 ml) in round bottom flask fitted with a reflux condenser or into a 1 litre autoclave and stirred to get clear solution. Raney Nickel (49 g) as slurry in isopropyl alcohol (70 ml,) was added at 25°C. Reaction mass was heated to 70-75°C and progress was monitored by HPLC. After completion of the reaction, the catalyst was filtered and the product was isolated by evaporation of isopropyl alcohol from the filtrate under reduced pressure. Yield: 30.8 g (quantitative); HPLC purity: 99%.
Example 6: Preparation of (+)-Amphetamine hydrochloride.
To the N-Boc protected (+)-amphetamine (30 g) at 0 °C, was added ethyl acetate (100 ml) containing 10% of dissolved hydrochloric acid. The reaction mass was stirred and the temperature was gradually raised to 25°C and the stirring was continued for 20 hours. The progress was monitored by TLC, after disappearance of the Boc-protected compound, the solvent was removed at reduced pressure and the residue was slurred in toluene (1000 ml) at ambient temperature. The product was filtered and dried under vacuum at 50°C to provide the product as a white solid in almost quantitative yield. Yield: 21-22 g; Chiral purity: 99.5%; HPLC purity: 99%.
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We claim:
1) A process for the preparation of amphetamine derivatives of formula (I)
comprising

a)

(II) or its pharmaceutically aceptable acid addition salt

b)


treatment of the N-protected compound of formula (III) with a reducing agent in presence of an organic solvent at an elevated temperature gave compound of formula (IV),

c)


deprotection with an acid in an organic solvent gave compound of formula (I) in high yield and purity.

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2) A process as claimed in claim 1 (a), wherem the solvent is selected from the group comprising of chlorinated solvent, alcohol and water.
3) A process as claimed in claim 1(a), wherein the base is selected from the group comprising of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and triethyl amine.
4) A process as claimed in claim 1 (b), wherein the reducing agent is raney nickel.
5) A process as claimed in claim 4, wherein the amount of raney nickel employed for reduction of compound (III) is between 1.4 and 1.6 times gram weight per gram weight of the compound of formula (III).
6) A process as claimed in claim 1(b), wherein the organic solvent is an alcohol or an ester selected from the group comprising of methanol, ethanol and isopropanol or ethyl acetate.
7) A process as claimed in claim 1(c), wherein the acid is a mineral acid or an organic acid,
8) A process as claimed in claim 7, wherein the mineral acid is hydrochloric acid and the organic acid is either trifluoroacetic acid or methanesulfonic acid.
9) A process as claimed in claim 1(c), wherein the solvent is selected from the group comprising of chlorinated solvents, esters, alcohols and ethers.
Dated this first (1st) day of July, 2009
(Signed),
Mukund K. Gur/jar Chief Scientific Officer Emcure Pharmaceuticals Ltd.