FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 & rule 13)
"A NOVEL PROCESS FOR THE PREPARATION OF (D,L)-THREO-RITALINIC ACID"
ZCL CHEMICALS LIMITED
215 ATRIUM, "C" WING, 8TH FLOOR
819-821, ANDHERI-KURLA ROAD, CHAKALA,
ANDHERI (EAST), MUMBAI-400 093,
MAHARASHTRA, INDIA.
(An Indian Organization)
The following specification particularly describes the invention and the manner in which it is to be performed.

"A NOVEL PROCESS FOR THE PREPARATION OF (D,L)-THREO-RITALINIC ACID"
FIELD OF THE INVENTION
The present invention relates to a process for the expedient preparation of (d,l)-threo-ritalinic acid of formula II from the mixture of mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide (fomula la) and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetamide (formula Ib).

BACKGROUND OF THE INVENTION
Chemical Name (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetic acid, popularly known as (d,l)-thzereo-ritalinic acid is a useful intermediate for the preparation of methylphenidate hydrochloride (INN). Methylphenidate is a psychostimulant drug approved for treatment of ADHD or attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It was first licensed by the FDA in 1955 for treating ADHD, prescribed from 1960, and became heavily prescribed in the 1990s, when the diagnosis of ADHD itself became more widely accepted. It is available worldwide with different brand names like Concerta®, Daytrana®, Metadate CD®, Metadate® ER, Methylin®, Quillivant™ XR, Ritalin LA®, Ritalin-SR®, Ritalin®.

Until the introduction of d-threo methylphenidate hydrochloride, (dexmethylphenidate hydrochloride, Focalin®) in 2002, all marketed forms of methylphenidate contained about 50:50 isomeric mixture of d-threo-methylphenidate and 1-threo methylphenidate in the form of hydrochloride salt. In 2007, a transdermal patch containing (d,l)-threo-methylphenidate (Daytrana®) was approved by the USFDA.
US patent no. 2,957,880 and 2,507,631 describe process in one of the embodiment that crude a-phenyl-a-piperidyl-(2)-acetamide having 30% threo isomer refluxed in 50% solution of potassium hydroxide in water. After cooling, the mass having increased content of threo isomer in α-phenyl-a-piperidyl-(2)-acetamide was filtered with suction and washed with water to isolate the compound which went under acid catalyzed hydrolysis by adding sulfuric acid to isolate α-phenyl-α-piperidyl-(2)-acetic acid having increased content of threo isomer.
Patrick, K.S., J. Med. Chem. 24:1237-1240 (1981), discloses the process, erythro- and -(d,l)-2-(4-methoxyphenyl)-2-(2'-piperidyl) acetamide hydrochloride is treated with 50% solution of potassium hydroxide in water for 4 days until an aliquot contained no more than 5% erythro isomer. But did not elaborate further conversion to the corresponding acetic acid derivative.
Synthetic methods using mixtures of threo- and erythro-α-phenyl-a-piperidyl-(2)-acetamide as raw materials for the preparation of threo enriched α-phenyl-α-piperidyl-(2)-acetic acid are described in U.S. Patent Nos. 2,838,519; 5,936,091; and in Deutsch et al. J. Med Chem., 39, 1201-1209 (1996). These methods disclose preparation of a-phenyl-a-piperidyl-(2)-acetic acid by treating threo- and erythro- α-phenyl-α-piperidyl-(2)-acetamide with 50% solution of potassium hydroxide in water to isolate threo enriched α-phenyl-α-piperidyl-(2)-acetamide followed by acid catalyzed hydrolysis to get threo enriched a-phenyl-α-piperidyl-(2)-acetic acid.

Burton W., Biochemistry, vol. 13 (25), 5164-5169 (1974), discloses kinetic studies on the alkali catalyzed hydrolysis and epimerization of model alkyl and hydroxyalkyl di- and tripeptide in which hydrolysis and epimerization observed by incubating glycyl-L-serine in either borate or phosphate complexes. However the cited article does not relate to the preparation of (&,\)-threo-nid\m\c acid or intermediates or derivatives thereof.
In general, above cited references involves epimerization as separate operation and isolation of intermediate followed by acid catalyzed hydrolysis as additional operation though the processes are not even capable to produce purer (d,\)-threo-ritalinic acid. Moreover such processes involve longer process time cycle, use of strong alkali and strong mineral acids at elevated or reflux temperature having severely corrosive and hazardous processing characteristics causing several potential base catalyzed or acid catalyzed side reactions; such process conditions are unfavorable for controlling the presence of organic impurities and result into a large volume of waste-water generation making the process less desirable for the large-scale industrial production.
Looking to the worldwide clinical usage of (d,l)-threo-methylphenidate, the multistep nature of converting mixed isomers of Formula (I) to the product of Formula(II) and the need to purify the intermediates of prior art procedures are still recognized as two very important drawbacks for this protocol from the economic and environmental viewpoints. Thus, there exist a need for an efficient and expedient process to prepare (d,l)-threo-ritalinic acid of high purity. Surprisingly, the scientists of the present invention have discovered a novel approach offering facile and direct conversion to (d,l)-threo-ritalinic acid from mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetamide without requiring isolation of threo enriched amide, acid hydrolysis and purification steps. The novel process achieves high yield and high purity and also involves short process cycle time, complete conversion of starting materials into the product,

recovery of excess raw materials and is restricting all identified individual organic impurities below 0.15% to meet the current guidelines issued by the International Council Of Harmonization (ICH).
Thus, present invention fulfills the need of the art and provides a direct, short, efficient and industrially applicable process for preparation of high purity (d,1)-(hreo-ritalinic acid in high yield.
OBJECT OF THE INVENTION
The object of the present invention is to provide an efficient and industrially advantageous process for preparation of (d,l)-threo-ritalinic acid of formula II by treating mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide (la) and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetamide (lb) with an inorganic base in alcohol.
Another object of the present invention is to convert by a novel process, the mixture of formula la and lb amide compounds to (d,l)-threo-ritalinic acid without apparent addition of water into the reaction mass.
Yet another object of the present invention is to suppress the esterification or reversible isomerization and restrict the side-reaction of conversion of formula II compound into its ester by-product below detection limit.
Yet another object of the present invention is to devise a process suitable to accept mixed isomeric amide (la and lb) as starting material and convert into substantially pure (d,l)-threo-ritalinic acid of formula II.
Yet another object of the present invention is to generate substantially pure (d,l)-threo-ritalinic acid of formula II, in which, starting material reaches to below

detection limit within short reaction time cycle ,combining the isomerization and amide hydrolysis in once-through process cycle.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of (d,l)-threo-ritalinic acid of formula II by treating mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide (la) and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetamide (lb) with a suitable solid inorganic base in C3-C8 alcohol at temperatures of 75 to 145°C; wherein process is capable to convert the mixture of formula la and lb to (d,1)-threo-ritalinic acid without apparent addition of water into the reaction mixture; the process also aims to suppress the esterification or reversible isomerization and restrict the side-reaction of conversion of formula II compound into its ester by-product below detection limit; permitting to convert mixed isomeric amide (la and lb) into substantially pure (d,l)-threo-ritalinic acid of formula II; and generate substantially pure (d,1)-threo-ritalinic acid of formula II in which starting material reaches to below detection limit within short reaction time cycle of about 3 hours or more as outline in the Scheme-1 below. Scheme-1


DETAILED DESCRIPTION OF THE INVENTION
All ranges cited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skilled in the art. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The present invention provides an efficient process for the preparation of (d,\)-threo-ritalinic acid of formula II.
According to one embodiment, the present invention provides a process for preparation of high purity product (d,l)-threo-ritalinic acid of formula II starting from mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide (la) and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetamide (lb) as shown below in Scheme-2. Scheme-2


According to the embodiment, mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl] acetamide (la) and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl] acetamide (lb) treated with a suitable solid inorganic base in a solvent.
The solid inorganic base used for the reaction can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate or mixtures thereof. The solvents which are useful for the reaction can be selected from C3-C8 alcohol such as 2-propanol, 1-butanol, 2-butanol, 2-methylpropan-l-ol, 1-pentanol, 2-pentanol, 2-ethyl hexanol and the like or mixtures thereof. Such solvent carf'be fresh or from a recycled lot of previous batch.
The temperature range for the conversion can be selected from 75-145°C, preferably 80-130°C. to facilitate faster conversion and the subsequent recovery and recycling of solvent or solvent mix employed in the process before work-up and isolation of the product.
According to another embodiment, the present invention is to convert by a novel process, the mixture of formula la and lb amide compounds to (d,l)-threo-ritalinic acid without apparent addition of water into the reaction mass.
According to another embodiment, the process gives substantially pure (d,\)-threo-ritalinic acid of formula II having all individual organic impurities below 0.15%.
According to yet another embodiment, the reaction is monitored by suitable analytical techniques to confirm the presence of starting material in (d,l)-threo-ritalinic acid of formula II. The suitable analytical technique such as spectrometry, high performance liquid chromatography and the like.
According to another embodiment, the inventors of present invention found the surprising analytical evidence which shows a cascade of facile conversion of

unwanted isomer of formula la into formula lb, which lb is further converted to compound of formula II along with simultaneous conversion of unwanted isomer of formula la to unwanted isomer of formula la-acid and further and final conversion of the process mass into desired compound of formula II. As shown in below scheme-3, at least four type of conversions involve in one reaction. Moreover that the end product i.e. (d,l)-threo-ritalinic acid obtained substantially pure having all individual organic impurities below 0.15% and starting material reaches to below detection limit.

According to another embodiment, the inventors of present invention found analytical evidence as given in below table with respect to above cited scheme-3 which shows all the conversions and respective rate of conversion into formula II.

Reaction progress monitoring(hplc) Erythro amide (%) Threo amide (%) Erythro acid (%) Threo acid (%)
Input analysis 56.81 42.99 - -
Batch 1 Reaction progress
Solvent = 5 volume
Alkali/inorganic Base = 3.0 mole After 2 hrs. 4.58 5.63 21.68 65.34

After 2.5 hrs. 1.80 2.51 20.10 71.38

After 3 hrs. 0.43 0.52 16.02 79.57

After 3.5 hrs. 0.13 0.24 13.96 82.60

After 4 hrs. 0.06 0.09 14.30 82.34

After 4.5 hrs. 0.05 0.05 14.00 82.88

After 5 hrs. 0.08 0.02 13.80 82.87

Isolated mass - 0.04 0.21 99.49
Batch 2
Solvent = 5 volume
Alkali/inorganic base = 8.17 mole After 2 hrs. 1.47 3.47 9.47 81.96

After 4 hrs 0.10 1.60 8.75 86.25

After 6 hrs. 0.02 1.44 7.57 87.44

Before aqueous slurrying - 0.13 0.22 99.33

after aqueous slurrying 0.01 0.06 0.07 99.70

Isolated, dried product - 0.04 0.06 99.72
According to another embodiment, process is capable of generating substantially pure (d,1)-threo-nta\mic acid of formula II having starting material i.e. mixture of formula la and lb below detection limit which is below 0.05%.
According to another embodiment, the process is capable to convert the mixture of formula la and lb to (d,l)-threo-ritalinic acid avoids apparent addition of water into the reaction mixture.
According to another embodiment, the process is capable to suppress the esterification or reversible isomerization and restrict the side-reaction of conversion of formula II compound into its ester by-product below detection limit.

According to another embodiment, the object of invention is to devise a process suitable to accept mixed isomeric amide (la and lb) as starting material and convert into substantially pure (d,l)-threo-ritalinic acid of formula II.
According to another embodiment, the process is capable to generate substantially pure (d,l)-threo-ritalinic acid of formula II in which starting material reaches to below detection limit within short time of 3 hours or more.
According to another embodiment, the obtained (d,l)-threo-ritalinic acid can be converted to its salts by conventional techniques.
According to yet another embodiment, the obtained (d,l)-threo-ritalinic acid or its salts can be converted to methylphenidate or its salts by conventional techniques.
The invention is further defined by reference to the following example describing the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLE 1: PREPARATION OF (D,L)-THEREO-RITALINIC ACID
Mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide and (2RS)-2-phmy\-2-[(2RS)-piperidin-2-yl]acetamide (100 g) was charged into the solution 1-butanol (400 g) and sodium hydroxide flakes (90 g) under stirring. The resulting mass was stirred vigorously and heated to 100-105°C and maintained for about 3-8 hours while monitoring the progress of reaction by conventional chromatographic analysis by TLC or HPLC. After reaction complies, it was cooled to 45-50°C. Thereafter water (450 g.) was added into the process mass followed by optional activated carbon treatment. The reaction mixture was filtered and pH was adjusted to 6.6±0.5 with concentrated hydrochloric acid. Thereafter the reaction mixture was stirred for 10-15 minutes while and filtered to get (d,l)-threo-ritalinic acid followed by water slurry treatment and dried to get pure (d,l)-threo-ritalinic acid (84 g) having all individual organic impurities below 0.15%.
EXAMPLE 2: PREPARATION OF (D,L)-THREO-RITALINIC ACID
Mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetamide (25 g) was charged into the solution 2-propanol (125 g) and sodium hydroxide flakes (37.5 g) under stirring. The resulting mass was stirred vigorously and heated to 80-85°C and maintained for about 3-8 hours while monitoring the progress of reaction by conventional chromatographic analysis by TLC or HPLC. After reaction complies, it was cooled to 45-50°C. Thereafter water (150 g.) was added into the process mass followed by optional activated carbon treatment. The reaction mixture was filtered and pH was adjusted to 6.6±0.5 with concentrated hydrochloric acid. Thereafter the reaction mixture was stirred for 10-15 minutes and filtered to get (d,l)-threo-ritalinic acid followed by water slurry treatment and dried to get pure (d,l)-threo-ritalinic acid (19 g) having all individual organic impurities below 0.15%.

WE CLAIM:
1. A process for the preparation of (d,l)-threo-ritalinic acid of formula II by treating mixture of (2RS)-2-phenyl-2-[(2SR)-piperidin-2-yl]acetamide and (2RS)-2-phenyl-2-[(2RS)-piperidin-2-yl]acetamide with a suitable solid inorganic base in C3-C8 alcohol at temperature 75-145°C;

wherein process is capable to convert the mixture of formula la and lb to (d,l)-threo-ritalinic acid without apparent addition of water into the reaction mixture; wherein process is capable to suppress the esterification or reversible isomerization and restrict the side-reaction of conversion of formula II compound into its ester by-product below detection limit;
wherein process is to devise a process suitable to accept mixed isomeric amide (la and lb) as starting material and convert into substantially pure (d,l)-threo-ritalinic acid of formula II; and
where in process is capable to generate substantially pure (d,l)-threo-ritalinic acid of formula II in which starting material reaches to below detection limit within short time of 3 hours or more. 2. The process according to claim 1, wherein solid inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate or mixtures thereof.

3. The process according to claim 1, wherein C3-C8 alcohol is selected from 2-propanol, 1-butanol, 2-butanol, 2-methylpropan-l-ol, 1-pentanol, 2-pentanol, 2-ethyl hexanol and the like or mixtures thereof.
4. The process according to claim 1, wherein preferable reaction temperature is 80-130°C.
5. The process according to claim 1, wherein reaction is monitored by suitable analytical techniques to confirm the presence of starting material in (d,1)-threo-ritalinic acid of formula II.
6. The process according to claim 1, wherein substantially pure (d,l)-threo-ritalinic acid of formula II having all individual organic impurities below 0.15%
7. The process according to claim 1, wherein substantially pure (d,l)-threo-ritalinic acid of formula II having starting material mixture of formula la and lb below detection limit which is below 0.05%.