• Field of the invention
The objective of the present invention relates to improved process for the manufacture of a (^-/^reo-ritalinic acid hydrochloride and /-rAreo-ritahnic acid hydrochloride in an optically pure form by the resolution of dl-threa-ritaimc acid using a chiral carboxyhc acid.
• Background of invention
Methylphenidate av^lable in the market to treat Attention Deficient Hyperactivity Disorder (ADHD) is dl-ihreo mixture. It is a controlled substance. Methylphenidate contains two chiral carbon atoms and so exists in four enantiomeric forms. Of all the forms, the studies of its //ireo-diastereomer revealed that d-threo isomer has been found to be more active and also showed significant metabolic difference than l-threo enantiomer.
To date, there have been several methods disclosed in the literature for preparing d-threo enantiomer of methylphenidate. For example, the process reported first by Patrick et.al. [The Journal of Pharmacology and Experimental Therapeutics, 241, 152-158 (1987)], describes the use of expensive resolving agent, I,r-binaphthyl-2,2'-diyl hydrogen phosphate in the resolution of £//-//?/-£o-methylphenidate. More efficient resolutions, using a 0,0-Diaroyltartaric acid or menthoxy-acetic acid or dibenzoyl-D-tartaric acid are disclosed in W09727176, GB97/00643, US 6100401, US 6121453, US 6162919 and US 6242464. Resolution of //^reo-methylphenidate may also be achieved by enzymatic hydrolysis methods proposed by Prashad (1998) [US7247730] and in WO98/25902.
U.S.2957880 discloses the resolution of erK^Aro-phenylpiperidyl acetamide using tartaric acid. This, however, must be followed by amide hydrolysis and equilibration at the benzylic centre, to give the threo isomer of the ritalinic acid.

In addition, U.S.2002/0019535 describes the manufacture of threo-ntalinic acid by resolution of ?/?reo-ritalinic acid hydrochloride using chiral base (5|)-(9-l-phenethylamine affording the product in 77% ee.
It would be desirable to find
1) a satisfactory substrate for resolution that did not involve handling of the active drug and
2) a more practical and efficient process to produce compound with high optical purity. Ritalinic acid in threo form might be a target. //zreo-Ritalinic acid contains a carboxylic group and a tertiary amino function in the moiety, due to which either chiral carboxylic acid or chiral organic base can be used for resolution. The t/-//;reo-enantiomer of ritalinic acid thus obtained can be converted to d-threo-mQthylphQnidate hydrochloride by reaction with methanol and hydrochloric acid.
The present invention provides an improved process for preparing d-and l-threo isomers of ritalinic acid of formula I & 11,

and its salt by resolution of dl-threo-ntaHimo, acid of the formula III using chiral carboxylic acid of the formula IV as the resolving agent.
3


The method of the present, invention is quite preferable and economical for the preparation of d-threo-rital'mic acid as an industrial procedure and gives d-threo-ritaiinic acid hydrochloride with high optical purity.
More particularly, the process involves the resolution of (i/-////*eo-ritalinic acid with (+)-dibenzoyl-D-tartaric acid to yield the desired tartrate salt of d-threo-isomer of ritalinic acid in the first step and the breaking of salt in the second step to obtain the hydrochloride form of the d-threo-isomcr with high optical purity, while the l-threo-isomer and the dibenzoyltartaric acid are recovered from the mother liquors as shown below:



• Objectives of the invention
The main objective of the present invention is to provide an improved process for the resolution of c//-//ireo-ritalinic acid
Another objective of the present invention is to provide an improved process for the preparation of d-threo-ritaiimc acid hydrochloride and l-thfeo-ritalimc acid hydrochloride by resolving the dl-threo-ntsdimc acid using chiral carboxylic acid as the resolving agent.
Another objective of the present invention is to provide an improved process for the preparation of d-tkreo-ritalinic acid hydrochloride by resolving the dl~threo-nta\imc acid involving the use of stoichiometric quantity of the resolving agent.
Still another objective of the present invention is to provide an improved process for the preparation of d-threo-nX2i\\mQ, acid hydrochloride by resolving the dUthreo-nXsMr^c acid with reduced process steps for isolating d-threo-xitsAmic acid in high optical purity of > 99%.
Yet another objective of the present invention is to provide an improved process for the preparation of t/-Mreo-ritalinic acid hydrochloride by resolving the dl-threo-ntaiimQ- acid involving the recovery of derivative of tartaric acid from the mother liquors with highest yield.
5

As a result, the present invention provides a simple but efficient, economical, less time consuming and less tedious method for producing ci-threo-niaiimc acid hydrochloride.
• Detailed description of the invention
Accordingly, the present invention provides an improved process for the preparation of d'threo-ntalkiic acid hydrochloride and /-r/^reo-ritalinic acid hydrochloride by resolution of rf/-/ftreo-ritalinic acid using chiraJ carboxylic acid which comprises of
(i) dissolving dl-threo-ntaiimc acid in a solvent, water mixture (60:40) and adding a
solution of an ester of tartaric acid in a solvent to the dissolved dl~threo-nia\imc
acid solution at a temperature in the range fom -10 °C to 100 °C for a period
ranging from 5 min to 5 h. (ii) heating the mass to reflux for a period ranging fi-om 15 min to 24 h and filtering it
through the hyflo bed and cooling the filtrate to a temperature in the range of
-10 °C to 40 °C to obtain a slurry containing solid mass of d-ihreo-ntalimc acid-
tartaric acid ester salt, (iii) maintaining the resulting slurry for a period ranging firom 30 min to 24 h and
filtering to obtain d-threo-ntaiiinc acid-tartaric acid ester salt, (iv) adding to the mother liquor, concentrated or dilute hydrochloric acid, solvent and
concentrating the mother liquor under vacuum by maintaining temperature 40 °C
to 100° C. (v) adding organic solvent to the concentrated mother liquor. (vi) cooling the mass to a temperature in ihe range of -15 ^C to 40 °C and filtering to
get /-^/ireo-ritalinic acid hydrochloride and the mother liquor containing the
resolving agent, (vii) adding organic solvent and water along with organic or inorganic acids to the
d-threo-ntsdinic acid-tartaric acid ester salt obtained in step (iii) and removing the
water present in the acid using the known methods, (viii) adding an organic solvent to the concentrated mass obtained in step (vii) under
stirring at a temperature range of -10 °C to 25 °C and filtering, to get the d-threo-
ritalinic acid hydrochloride and the mother liquor containing the resolving agent.

(ix) concentrating the mother liquors obtained in step (vi) and (viii) basifying and acidifying by conventional methods and filtering the resolving agent.
The dl- threo-ntaMiiic acid used in step (i) may be prepared through multi-step process in which 2-chloropyridine and benzyl cyanide initially are coupled to form a-pyrid-2-yl-phenylacetonitrile. The resulting a-pyridyl-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield a-pyrid-2-ylphenyIacetaraide which in turn is catalytically hydrogenated to yield a-piperid-2-ylphenyiacetamide and then is hydrolysed and epimerized to dl-threo-nXs^inic acid. The solvent used in the step (i) along with water may be selected from organic solvents. Hie solvent used to dissolve ester of tartaric acid may be selected from organic solvents. Conventional esters of tartaric acid used may include dibenzoyltartaric acid and ditoluoyltartaric acid, the preferred one being (+)-dibenzoyltartaric acid of 0.2 to 1.6 eq to that of ritalinic acid, preferably, 1.06 eq in a solvent, preferably methanol adding at a temperature ranging preferably below 50 °C, for a period preferably ranging from 5 min to 5 h. Heating the mass in step (ii) at reflux temperature preferably in 1 h to 2 h and filtering the mass through hyflo bed. The filtrate is cooled to a temperature preferably 20 °C to 25 ^C.
The resulting mass of step (iii) is maintained under stirring preferably for 13 h before filtering the d- threo-ntaWmc acid-tartaric acid ester salt.
The mother liquor of step (iii) is concentrated imder vacuiun at a temperature preferably 70 ''C to 80 ''C after the addition of concentrated or dilute hydrochloric acid along with solvent preferably toluene. The solvent used in step (v) may be selected from water, aliphatic ketones or alcohols, the preferred one being acetone.
The mass obtained is cooled in step (vi) to a temperature in the range -15 °C to 40 °C, preferably 10 ""C before filtering the Uhreo-ntBivoic acid hydrochloride.
in step (vii), the solvents like aliphatic ketones or aromatic ketones or alcohols or aromatic/aliphatic hydrocarbons preferably toluene are added to d~threo-ti\sA\Bic acid-

tartaric acid ester salt along with organic or inorganic acids, preferably hydrochloric acid and heated to evaporate the solvent.
In step (viii), solvents like aliphatic ketones or aromatic ketone or alcohols prefefrably acetone is added under stirring for preferably 15 min to 30 min at a temperature range of -10 X to 25 °C preferably 5 °C to 10 "C whi\e filtering the d-threo-ntaVmic acid salt. The mother liquors of steps (vi) and (viii) are concentrated together, diluted with water and basified. The ester of tartaric acid formed was filtered after acidification.
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 I
dl-threo-^taimc acid : 100 g
(+)-Dibenzoyl-D-tartaric acid : 182 g
Methanol : 2.3 L
Water :1.8L
Acetone : 175 mL
HCl : 65 mL
Toluene : 450 mL
J/-//ir^o-Ritalinic acid (100 g, 0.456 mole) was dissolved in methanol-water mixture (1.8 L and L6 L) at room temperature and stirred for 15 min.
(+)-Dibenzoyl-D-tartaric acid (182 g, 0.483 moles) was dissolved in 300 mL of methanol and was added at a temperature below 50 *C in 30 min. The resulting mass was heated to reflux temperature 78 °C to 85 °C and maintained for 1 h to 2 h. The mass was filtered through hyflo bed and washed with 200 mL of water-raethanol mixture (1:1). The filtrate was cooled to 20 °C to 25 °C and maintained for 13 h. The precipitated material out was
8

filtered and washed with 200 mL of chilled water-methanol mixture (3:1) to obtain 132 g d-threo-r\\a\in\c acid-dibenzoyl tartaric cid salt.
The mother hquor obtained was treated with 35 mL of cone, hydrochloric acid, 225 mL of toluene and concentrated under vacuum by maintaining a temperature of 70 °C to 80 °C. On addition of 100 mL of acetone to the residue and on cooling to 10 '^C followed by filtration 45 g of/-/Ar^o-ritalinic acid hydrochloride was isolated.

Respective mother liquors obtained from the d-threo-nia\m\c acid hydrochloride and the l-threo-ritalmc acid hydrochloride were concentrated, basified and acidified to recover (+)-dibenzoyl-D-tartaric acid in 90% yield showing optical rotation of-113° and melting point 88 ^C-93°C.
9

spectroscopic interpretation
Th? structure of the product, d-threo-ntalmic acid hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR(cm*)(KBr)
OH str. of bonded COOH group at 3150-2710, HN-Hstr. at 2567, 2509, C = O str. of COOH group at 1709, benzenoid bands at 1585, 1456, C-N str. at 1396, C-O str. at 1182, C-H out ofplane bending of mono-substituted benzene ring at 729,704.
b) *H NMR (DMSO-dfi, 300 MHz) (6H)
1.24-1.66 (6H, m, -NH-<:H2-CH2-CH2 of piperidyl ring), 1.96 (IH, s, Ha of
t I
HC—COOH CH—COOH
—HN-CH-CH—CH; ~HN—CH-CH-
H" ), 3.29 (IH, d, Hb of Bb ) [where Ha and Hb are diastereotopic
protons], 3.73 (IH, s, -CH-CH-NH-), 4.08 (IH, d, Ph-CH-COOH), 7.27-7.43 (5H, m, aromatic protons), 8.67 (IH, bs, NH proton), 9.73 (1H, bs, COOH proton).
c) "C NMR (DMSO-d6,300 MHz) (5^)
10
21.29 (-NH-CH2-CH2-CH2X 21.44 (-NH-CH-CH2), 25.50 (-NH-CH2-CH2), 44.56 (-NH~CH2-), 53.21 (Ph-CH-CH-NH), 56.69 (Ph^H-COOH), 127.85 - 134.89 (aromatic protons), 172.38 (CH-COOH).

• Advantages of the invention
1. The process uses resolving agent which is easily available
2. The resolving agent used can be recovered almost quantitatively.

3. Resolution process is simple as it requires lesser number of steps and the d-threo-riXaMnic acid is obtained in >99 % optical purity in >90%of theoretical yield (first crop).
4. The process is very economical and useful for conimercial production as the variabJe cost is very low.
We Claim
1. An improved process for the preparation of d-ihreo~Rita\imc acid & l-threo-Ritalinic acid of the formula I& W and their salts

by resolution of dl-threo-ritalinic acid of formula 111 using ester of tartaric acid of formula IV which comprises of

(i) dissolving dl-threo-ntaWmc acid in a solvent, water mixture (^0:40) and adding a solution of an ester of tartaric acid dissolved in an organic solvent to the solution

at a temperature in the range from -10 °C to 100 °C for a period ranging fit)m 5
min to 5 h. . , . _
(ii) heating the resulting mass to reflux for a period ranging from 15 min to 24 h and
filtering it through the hyflo bed, cooling the filtrate to a temperature in the range
of-10 °C to 40 ^C to obtain a slurry containing 5olid mass of d-ihreo-ntalmc
acid-tartaric acid ester salt, (iii) maintaining the resulting slurry for a period ranging from 30 min to 24 h and
filtering to obtain a mother liquor, separating d-threo-ritalmic acid-tartaric acid
ester complex, (iv) adding to the mother liquor, concentrated or dilute hydrochloric acid and
concentrating the mother liquor under vacuum by maintaining the temperature
40'^Ctol00°C. (v) adding organic solvent to the concentrated mother liquor, (vi) cooling the mass to a temperature in the range of -15 °C to 40 °C and filtering to
get /-/^reo-ritalinic acid hydrochloride and the mother liquor containing resolving
agent. (vii) adding an organic solvent along with organic or inorganic acids to the d-tkreo~
ritalinic acid-tartaric acid ester salt obtained in step (iii) and removing water
present in the acid using known methods, (viii) adding an organic solvent to the concentrated mass obtained in step (vii) at a
temperature range of ^10 °C to 25 °C and filtering the d-tkreo~nta\\mc acid
hydrochloride and separating the mother Uquor containing the resolving agent, (ix) concentrating the mother liquors obtained in step (vi) and (viii), basifying and
aciditying by conventional methods and filtering the resolving agent.
2. , An improved process as claimed in claimt wherein the