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Title:
IMPROVED PROCESS FOR THE PREPARATION OF D-THREO-RITALINIC ACID HYDROCHLORIDE BY RESOLUTION OF DL-THREO-RITALINIC ACID USING CHIRAL CARBOXYLIC ACID
Document Type and Number:
WIPO Patent Application WO/2010/128517
Kind Code:
A1
Abstract:
The invention disclosed in this application relates to an improved process for the manufacture of d-threo-ritalinic acid hydrochloride and l-threo-ritalinic acid hydrochloride in an optically pure form by the resolution of dl-threo-ritalinic acid using a chiral carboxylic acid The d-threo-ritalinic acid hydrochloride prepared by the process of the present invention on esterifϊcation gives d-threo-methylphenidate, a very well known CNS stimulant.

Inventors:
PRAKASAM, Tangirala (Plot 12, 3rd Floor "T1"Spripriyas Manasa,V.V. Koil Street,Chinmaya Nagar, Chennai 2, 600 09, IN)
KUMAR, Borkatte, Narasimha, Hitesh (103 Street, A.P. Block14th Sector, K.K. Nagar, Chennai 8, 600 07, IN)
PERUMAL, Sangu (143 Pandi Durai Thevar Street, NH-1 LIG, Maraimalai Nagar, Kanchipuram Dt. 9, 603 20, IN)
LOGANATHAN, Kothandapani (3 Chinmaya Colony, Rajakilpakkam, Chennai 3, 600 07, IN)
Application Number:
IN2009/000378
Publication Date:
November 11, 2010
Filing Date:
July 03, 2009
Export Citation:
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Assignee:
MALLADI DRUGS & PHARMACEUTICALS LTD. (No. 9, G.S.T. RoadSt. Thomas Mount, Chennai 6, 600 01, IN)
PRAKASAM, Tangirala (Plot 12, 3rd Floor "T1"Spripriyas Manasa,V.V. Koil Street,Chinmaya Nagar, Chennai 2, 600 09, IN)
KUMAR, Borkatte, Narasimha, Hitesh (103 Street, A.P. Block14th Sector, K.K. Nagar, Chennai 8, 600 07, IN)
PERUMAL, Sangu (143 Pandi Durai Thevar Street, NH-1 LIG, Maraimalai Nagar, Kanchipuram Dt. 9, 603 20, IN)
LOGANATHAN, Kothandapani (3 Chinmaya Colony, Rajakilpakkam, Chennai 3, 600 07, IN)
International Classes:
C07B57/00
Foreign References:
US20020019535A1
US6242464B1
Attorney, Agent or Firm:
MALLADI DRUGS & PHARMACEUTICALS LTD. (No. 9, G.S.T. RoadSt. Thomas Mount, Chennai 6, 600 01, IN)
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Claims:
• 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-ήta\inic acid is obtained in >99 % optical purity in >90%of theoretical yield (first crop).

4. The process is very economical and useful for commercial production as the variable cost is very low.

We Claim

1. An improved process for the preparation of d-threo-Bάtalinic acid & l-threo- Ritalinic acid of the formula I& II and their salts

J-//?reσ-Ritalinic acid /-tfweo-Ritalinic acid (Formula 1) (Formula II) by resolution of dl-threo-ritalinic acid of formula HI using ester of tartaric acid of formula IV which comprises of

J/-//ireo-Ritalinic acid (+)-Dibenzoyl-D-tartaric acid monohydrate (Formula III) (Formula IV)

(i) dissolving acid in a solvent, water mixture (60:40) 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 0C to 100 0C for a period ranging from 5 min to 5 h. (U) 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 0C to 40 °C to obtain a slurry containing solid mass of d-threo-nta\mic 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-ήtalimc 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 0C tO lOO 0C.

(v) adding organic solvent to the concentrated mother liquor, (vi) cooling the mass to a temperature in the range of —15 0C to 400C and filtering to get /-/Areo-ritalinic acid hydrochloride and the mother liquor containing resolving agent . (vii) adding an organic solvent along with organic or inorganic acids to the d-threo- 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 0C to 25 0C and filtering the t/-fΛreo-ritalinic acid hydrochloride and separating 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.

2. An improved process as claimed in claiml wherein the f//-/Λrø>-ritalinic acid used is selected from derivatives of chiral tartaric acid and the solvent used is selected from organic solvents and water, preferred is methanol and water mixture (60:40) Ester of tartaric acid used is selected from dibenzoyltartaric acid and ditoluoyltartaric acid, preferably (+)-dibenzoyl-D-tartaric acid, the amount of ester used is 0.2 to 1.6 eq to that of the base used, preferably 1.06 eq. The organic solvent used is methanol and the addition is carried at a temperature in the range of -10 0C to 100 0C preferably below 50 0C for a period ranging from 5 min to 5 h preferably 30 min.

3. The improved process as claimed in claims 1 to 2 wherein the mass is heated to reflux temperature of the solvent for a period ranging from 15 min to 24 h preferably 2 h and filtering it through the hyflo bed, the filtrate is cooled to a temperature in the range of-10 0C to 40 0C preferably 20 0C to 25 °C to obtain a slurry containing solid mass of d-threo-ήtalimc acid-tartaric acid ester salt.

4. The improved process as claimed in claims 1 to 3 wherein the step (iii) slurry is maintained for a period ranging from a period 30 min to 24 h preferably 13 h to obtain a mother liquor, separating d-threo-ήtaliϊάc acid— tartaric acid ester salt.

5. The improved process as claimed in claims 1 to 4 wherein the concentrated hydrochloric acid is added along with toluene to the mother liquor and the mass is concentrated under vacuum at a temperature 70 0C to 80 °C, the organic solvent used in step (v) is acetone.

6. The improved process as claimed in claims 1 to 5 wherein the cooling in step (vi) is effected in the range -15 0C to 400C preferably 10 0C.

7. The improved process as claimed in claims 1 to 6 wherein the organic solvent added to the step (vii) is toluene and the acid is an organic or inorganic acid, preferably hydrochloric acid.

8. The improved process as claimed in claims 1 to 7 wherein the solvent used in step (viii) is selected from water, aliphatic ketones or alcohols, preferably acetone. The improved process as claimed in claims 1 to 8 wherein the mother liquors are step (vi) and step (viii) are concentrated together, diluted with water and basified. The ester of tartaric acid formed is filtered after acidification.

Description:
IMPROVED PROCESS FOR THE PREPARATION OF d-tkreo-WTALINlC

ACID HYDROCHLORIDE BY RESOLUTION OF dl-threø-RΪTALINIC ACID

USING CHmAL CARBOXYLIC ACID

The following specification describes the nature of the invention and the manner in which it is to be performed: • Field of the invention

The objective of the present invention relates to improved process for the manufacture of a d-threo-ήtalinic acid hydrochloride and /-fAreo-ritalinic acid hydrochloride in an optically pure form by the resolution of dl-threo-ήta\iτnc acid using a chiral carboxylic acid.

• Background of invention

Methylphenidate available in the market to treat Attention Deficient Hyperactivity Disorder (ADHD) is dl-threo 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 rAreo-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, l,l'-binaphthyl-2,2'-diyl hydrogen phosphate in the resolution of dZ-fArø?-methylphenidate. More efficient resolutions, using a O,O-Diaroyltartaric acid or menthoxy-acetic acid or dibenzoyl-D-tartaric acid are disclosed in WO9727176, GB97/00643, US 6100401, US 6121453, US 6162919 and US 6242464. Resolution of /Areo-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 ery/λro-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-ήtalinic acid by resolution of fλreo-ritalinic acid hydrochloride using chiral base (^-f-^-1-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. /Areø-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 rf-/Λreo-enantiomer of ritalinic acid thus obtained can be converted to rf-fΛreo-methylphenidate hydrochloride by reaction with methanol and hydrochloric acid.

The present invention provides an improved process for preparing d-md l-threo isomers of ritalinic acid of formula I & π,

</-iΛreo-Ritalinic acid /-fλreo-Ritalinic acid

(Formula I) (Formula TS)

and its salt by resolution of J/-*Λrø>-ritalinic acid of the formula III using chiral carboxylic acid of the formula FV as the resolving agent . dl-threo-Ritalinic acid (+)-Dibenzoyl-D-tartaric acid monohydratε (Formula Ul) . (Formula IV)

The method of the present invention is quite preferable and economical for the preparation of £/-#?rø?-ritalinic acid as an industrial procedure and gives d-threo-ήtalinic acid hydrochloride with high optical purity.

More particularly, the process involves the resolution of <#-.Λrø>ritaiinic acid with (+)- dibenzoyl-D-tartaric acid to yield the desired tartrate salt of d-threo-i ' somsτ of ritalinic acid in the first step and the breaking of salt in the second step to obtain the hydrochloride form of the with high optical purity, while the l-threo- isomer and the dibenzoyltartaric acid are recovered from the mother liquors as shown below:

d-threo- Ritalinic acid. DBTA salt crude l-threo- Ritalinic acid. DBTA salt (in mother liquor ML 1 )

etone) d-threo- Ritalinic acid. DBTA salt d-threo- Ritalinic acid hydrochloride ML 3 (DBTA in acetone) l-threυ- Ritalinic acid. DBTA salt (in mother liquor ML 1 ) l-threo- Ritalinic acid hydrochloride

(+)-Dibenzoyl-D-tartaric acid monohydrate

• Objectives of the invention

The main objective of the present invention is to provide an improved process for the resolution of dl-threo-ήtalinic acid

Another objective of the present invention is to provide an improved process for the preparation of ^-^reo-ritalinic acid hydrochloride and /-tf?ra?-ritalinic acid hydrochloride by resolving the dl-threo-ήtalinic 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-lhreo-ήtaϊinic acid hydrochloride by resolving the dl-threo-ήta\mic 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-ήtaYmic acid hydrochloride by resolving the dl-threo-ήtalimc acid with reduced process steps for isolating d-threo-ήt&linic acid in high optical purity of > 99%.

Yet another objective of the present invention is to provide an improved process for the preparation of d-threo-ήtalinic acid hydrochloride by resolving the dZ-?/?reϋ-ritalinic acid involving the recovery of derivative of tartaric acid from the mother liquors with highest yield. As a result, the present invention provides a simple but efficient, economical, less time consuming and less tedious method for producing d-threo-ήtalm ' ic acid hydrochloride

β Detailed description of the invention

Accordingly, the present invention provides an improved process for the preparation of d-threo-ήta\inic acid hydrochloride and /-//weø-ritalinic acid hydrochloride by resolution of dl-threo-ήtaYmic acid using chiral carboxylic acid which comprises of

(i) dissolving dl-threo-ήtalinic acid in a solvent, water mixture (60 40) and adding a solution of an ester of tartaric acid in a solvent to the dissolved d/-.Αra?-ritalinic acid solution at a temperature in the range from -10 °C to 100 0 C for a period ranging from 5 min to 5 h (ii) heating the mass to reflux for a period ranging from 15 min to 24 h and filtering it through the hyflo bed and cooling the filtrate to a temperature in the range of

-10 0 C to 40 °C to obtain a slurry containing solid mass of d-threo-ήt&Ymi ' c acid- tartaric acid ester salt (iii) maintaining the resulting slurry for a period ranging from 30 min to 24 h and filtering to obtain d-threo-ήtaYmic 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 the range of -15 °C to 40 °C and filtering to get /-fΛrø?-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-ήta\inic 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 0 C to 25 0 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- J/zreø-ritalinic acid used in step (i) may be prepared through multi-step process in which 2-chloropyridine and benzyl cyanide initially are coupled to form α-pyrid-2-yl- phenylacetonitrile. The resulting α-pyridyl-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield α-pyrid-2-ylphenylacetamide which in turn is catalytically hydrogenated to yield α-piperid-2-ylphenylacetamide and then is hydrolysed and epimerized to tll-threυ-ήtdXmic acid. The solvent used in the step (i) along with water may be selected from organic solvents. The solvent used to dissolve ester of tartaric acid may be selected from organic solvents. Conventional esters of tartaric acid used s 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 hyfϊo bed The filtrate is cooled to a temperature preferably 20 °C to 25 0 C.

The resulting mass of step (iii) is maintained under stirring preferably for 13 h before filtering the d- acid-tartaric acid ester salt.

The mother liquor of step (iii) is concentrated under vacuum at a temperature preferably 70 °C to 80 0 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 0 C before filtering the 1-threo- ή tΑXmιc 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- ή tύimc 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 preferably acetone is added under stirring for preferably 15 min to 30 min at a temperature range of -10 °C to 25 0 C preferably 5 0 C to 10 °C while filtering the d-threo-ήtalinic 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 1

(+)-Dibenzoyl-D-tartaric acid : 182 g

Methanol : 2.3 L

Water : 1.8 L

Acetone : 175 mL

HCl : 65 mL

Toluene : 450 mL

J/-//weø-Ritalinic acid (100 g, 0.456 mole) was dissolved in methanol-water mixture (1.8 L and 1.6 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-methanol mixture (1:1). The filtrate was cooled to 20 °C to 25 °C and maintained for 13 h. The precipitated material out was filtered and washed with 200 mL of chilled water-methanol mixture (1:1) to obtain 132 g d-threo-ήtalinic acid-dibenzoyl tartaric cid salt.

The mother liquor obtained was treated with 35 mL of cone, hydrochloric acid, 225 mL of toluene and concentrated under vacuum by maintaining a temperature of 70 0 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 /-/Arø?-ritalinic acid hydrochloride was isolated.

Purity by HPLC : 99.78%

Chiral purity : 99.05%

Yield : 90% tnp : 236 °C - 240 0 C

MD : - 88.5° (c = 2% in methanol)

To 132 g of d-threo-ήta\irύc acid-dibenzoyl tartaric acid salt, toluene 225 mL, 100 mL water and 30 mL of 35% hydrochloric acid were added and concentrated under vacuum by maintaining temperature of 60 0 C to 65 °C. On addition of 75 mL of acetone to the residue and on cooling to 5 °C to 10 °C followed by filtration, 46 g of d-threo-ήXdXvcάc acid hydrochloride was obtained.

Purity by HPLC : 99.92%

Chiral purity : 99.95%

Yield : 92% mp : 238 °C - - 240 °C

[α] D : + 89.08° (C = 2% in methanol)

Respective mother liquors obtained from the d-threo-ήiaXimc acid hydrochloride and the l-threo-ύXaXvcάc 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. Spectroscopic interpretation

The structure of the product, d-threo-ήta\inϊc acid hydrochloride was confirmed with the help of the following spectroscopic data.

a) IR (cm 1 ) (KBr)

O-H str. of bonded COOH group at 3150-2710, HN-H str. 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 of plane bending of mono-substituted benzene ring at 729,704.

b) 1 H NMR (DMSO-Cl 6 , 300 MHz) (δ H ) ring), 2.96 (IH, s, Ha of- [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 (IH, bs, COOH proton).

c) 13 C NMR (DMSO-c.6,300 MHz) (δ c )

21.29 (-NH-CH 2 CH 2 -CH 2 ), 21.44 ( NH-CH-CH 2 ), 25.50 ( NH-CH 2 -CH 2 ), 44.56 ( NH-CH 2 -), 53.21 (Ph-CH-CH-NH), 56.69 (Ph-CH-COOH), 127.85 - 134.89 (aromatic protons), 172.38 (CH-COOH).

d) Mass spectrum (EI)

Jt

[M] + - at m/z 220(<l), [M +" - CO 2 ] at m/z 175(2), [M + - - C 5 H 9 N] at m/z 136(2), O ^^ at m/ z 84(100), tropylium cation at m/z 91(11), [m/z 84 - (CH 2 N)] at m/z 56(21).