An Efficient Process For Synthesis Of Dexmethylphenidate


Updated about 2 years ago

Abstract

The present invention provides a simple and cost effective method for synthesis of dexmethylphenidate. The undesired l-threo-2-phenyl-2-piperidyl-2-acetamide (II) obtained during the synthesis of dexmethylphenidate is racemized to give a racemic mixture of dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (IV) which is then recycled to give dexmethylphenidate (I).

Information

Application ID 2378/MUM/2009
Invention Field CHEMICAL
Date of Application 2009-10-12
Publication Number 05/2012

Applicants

Name Address Country Nationality
EMCURE PHARMACEUTICALS LIMITED, EMCURE HOUSE, T-184, M.I.D.C., BHOSARI, PUNE-411026, INDIA. India India

Inventors

Name Address Country Nationality
GURJAR MUKUND KESHAV EMCURE HOUSE, T-184,M.I.D.C., BHOSARI, PUNE-411026, INDIA India India
MAIKAP GOLAKCHANDRA SUDARSHAN EMCURE HOUSE, T-184,M.I.D.C., BHOSARI, PUNE-411026, INDIA India India
CHAVAN ANIL BHAUSAHEB EMCURE HOUSE, T-184,M.I.D.C., BHOSARI, PUNE-411026, INDIA India India
GUNDECHA SACHIN SURESH EMCURE HOUSE, T-184,M.I.D.C., BHOSARI, PUNE-411026, INDIA India India
MEHTA SAMIT SATISH EMCURE HOUSE, T-184,M.I.D.C., BHOSARI, PUNE-411026, INDIA India India

Specification

FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"AN EFFICIENT PROCESS FOR SYNTHESIS OF DEXMETHYLPHENIDATE"
Emcure Pharmaceuticals Limited.,
an 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 DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to a process for preparation of dexmethylphenidate (I) by utilizing the undesired l-threo-2-phenyI-2-piperidyl-2-acetamide (II) or an enriched mixture containing the undesired isomer. The present invention, particularly, relates to method for the preparation of dexmethylphenidate (I) by racemization of the undesired l-threo-2-phenyl-2-piperidyl-2-acetamide or its enriched mixture by treatment with a base and N-halosuccinimide followed by hydrogenation and treatment with a base to give the dl-threo racemate which is then resolved and converted to dexmethylphenidate of formula (I).
BACKGROUND OF THE INVENTION
Dexmethylphenidate, chemically known as (2R,2'R)-(+)-Methyl-2-phenyl-2-piperidyl-2-acetate of formula (I), is the d-threo-enantiomer of racemic methylphenidate. Dexmethylphenidate marketed as its hydrochloride salt, under the brand name 'Focalin' is a dopamine uptake inhibitor and a central nervous system (CNS) stimulant. Biochemistry Pharmacology 1961, 8, 263-268 discloses that among the threo and erythro stereoisomers of methylphenidate, only the threo-isomer displays CNS stimulant properties. Further, Organic Process Research & Development 2000, 4, 55-59 also mentions that dexmethylphenidate hydrochloride is about 5 to 38 times more active than its corresponding (S, S)-dexmethylphenidate hydrochloride.

Various researchers have attempted to synthesize the active pharmaceutical ingredient dexmethylphenidate of formula (I) which is chemically known as (2R, 2'R)-(+)- Methyl-2-phenyl-2-piperidyl-2-acetate.
Dexmethylphenidate synthesis was first disclosed in US 2,838,519 and comprises
resolution of erythro-2-phenyl-2-piperidineacetamide to obtain (2R, 2'S)-2-phenyl-2-

piperidineacetamide. Herein, the undesired isomer gets carried away in the mother liquor and is not recycled, thereby lowering the overall yield.
US 5,965,734 discloses the preparation of dexmethylphenidate by optical resolution of threo-2-phenyl-2-piperidine acetamide, however, the said patent is silent about the undesired isomer which passes into the mother liquor, hence, the process is not cost-effective and not suitable for commercial purpose.
Methods reported in various patents like US 2,507,631, US 2,838,519, US 2,957,880, US 5,936,091 and WO 01/27020 disclose that dexmethylphenidate is obtained by reaction of 2-chloropyridine with phenyl acetonitrile in the presence of sodium amide as base followed by hydrolysis of the resulting nitrile and hydrogenation of the pyridine ring to piperidine. But none of these prior art references disclose a method for reconversion of the undesired l-threo-2-phenyl-2-piperidyl-2-acetamide (II) to the desired dexmethylphenidate of formula (I).
WO 2004080959 discloses a process for preparing dexmethylphenidate comprising resolution of N-protected threo-ritalinic acid with 1-arylethylamine to get the N-protected (R,R) enriched ritalinic acid followed by deprotection and esterification to obtain dexmethylphenidate of formula (I).
N-protected threo-ritalinic acid is obtained by treatment of 1 -(phenylglyoxylyl) piperidinearenesulfonylhydrazone with an inorganic base in the presence of phase transfer catalyst to obtain 7-phenyl-l-azabicyclo [4.2.0] octan-8-one which in turn is treated with hydrochloric acid to give methylphenidate. The product is N-protected with di-tert-butyl dicarbonate and then treated with an inorganic base to obtain threo-N-boc-ritanilic acid. This PCT application discloses a method for recycling of the erythro N-boc ritalinic acid from the mother liquor by a process of acidification and esterification but nowhere mentions a process for recycling of the undesired l-threo-2-phenyl-2-piperidyl-2-acetamide from the mother liquor of the final step in which dexmethylphenidate (I) is isolated.

WO 2008125914 discloses a method for resolution of threo-methylphenidate hydrochloride with a chiral acid like di-O-O'-aroyl tartaric acid; however, due to the absence of any method for recycling of the undesired isomer, the method becomes commercially unviable.
Further, there are several references such as Journal of Labelled Compd. Radiopharm. 1982, 19, 485-490; US 6,100,401; US 6,121,453; US 6,162,919 and US 6,242,464 which disclose resolution methods for threo-methylphenidate, however, none of these references disclose a method for recycling of the undesired 1-threo isomer of threo-methylphenidate, thereby making the overall process less attractive for commercial scale.
It is clearly evident from the above that prior art methods do not provide a method for recycling of the undesired l-threo-2-phenyl-2-piperidyl-2-acetamide (II) or an enriched mixture for preparing dexmethylphenidate (I). Such prior art methods result in high production cost thereby making such processes commercially unviable.
The present inventors have developed a method for re-utilization of the undesired 1-threo-2-phenyl-2-piperidyl-2-acetamide (II) due to which the resulting process becomes cost-effective and commercially viable. Further, in addition to being cost effective, the developed method is also simple and environmental friendly.
OBJECT OF THE INVENTION
An object of the present invention is to provide a commercially viable process for synthesis of dexmethylphenidate (I) by recycling the undesired isomer l-threo-2-phenyl-2-piperidyl-2-acetamide(II).
Another object of the present invention is to provide a simple cost effective process for racemization of 1- threo-2-phenyl-2-piperidyl-2-acetamide (II).

SUMMARY OF THE INVENTION
In their endeavor to prepare a simple, cost effective method for the synthesis of dexmethylphenidate, the present inventors have developed a process for recycling of the undesired 1-threo isomer of 2-phenyl-2-piperidyl-2-acetamide by racemization, in presence of a base and N-halosuccinimide followed by catalytic hydrogenation in an organic solvent and treatment with a base to give dl-threo isomer of 2-phenyl-2-piperidyl-2-acetamide (V).
An aspect of the invention relates to providing a cost effective method for the synthesis of dexmethylphenidate of formula (I) comprising treatment of 1-threo isomer of α-phenyl-α-piperidyl-2-acetamide of formula (II) or its enriched mixture with a inorganic base in an organic solvent, subsequently treating with N-halosuccinirnide and an organic base, and catalytic reduction to obtain dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide which is then treated with a base to give dl-threo-2-phenyl-2-piperidyl-2-acetamide, resolution of dl-threo-2-phenyl-2-piperidyl-2-acetamide followed by treatment with an alcohol in presence of an acid gives dexmethylphenidate of formula CD-DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a simple, economical and commercial viable process for the preparation of dexmethylphenidate.
Dexmethylphenidate of formula (I) is conventionally prepared by partially hydrolyzing 2-phenyl-2-pyridyl-2-acetonitrile to 2-phenyl-2-pyridyl-2-acetamide followed by a step of hydrogenation to give dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (TV), which is then treated with a base to give dl-threo-2-phenyl-2-piperidyl-2-acetamide (V) which on resolution gives d-threo-2-phenyl-2-piperidyl-2-acetamide (VI). Further, treatment with methanol in presence of an acid gives d-threo-Methylphenidate also known as dexmethylphenidate of formula (I).

The undesired 1-threo isomer of 2-phenyl-2-piperidyl-2-acetamide (II) passes into the mother liquor along with some uncrystallized d-threo isomer of formula (VI) to give an enriched mixture of the undesired 1-threo isomer of 2-phenyl-2~piperidyl-2-acetamide (II).
The present invention provides a method for recycling of the undesired isomer 1-threo isomer of 2-phenyl-2-piperidyl-2-acetamide (II) remaining in the mother liquor along with uncrystallized d-threo isomer to dexmethylphenidate of formula (I), as disclosed in Scheme I.

Scheme I: Method for preparation of Dexmethylphenidate (I) by recycling of the undesired l-threo-2-phenyl-2-piperidyl-2-acetamide (II)
The simple, cost-effective and commercially viable method of preparing dexmethylphenidate comprises of recycling the undesired 1-threo isomer of 2-phenyl-2-piperidyl-2-acetamide or an enriched isomer containing the same comprising treatment of the undesired isomer (H) with a base followed by N-halosuccinimide to provide a

compound of formula (HI), which is hydrogenated catalytically to give dl-erythro-threo mixture of formula (IV). Finally the dl-erythro-threo is epimerized to the corresponding dl-threo mixture by treatment with a base in an organic solvent and in subsequent steps to dexmethylphenidate (I).
In an embodiment, 1-threo isomer of 2-phenyl-2-piperidyl-2-acetamide or an enriched isomer of formula (II) is treated with a base preferably an inorganic base in an organic solvent.
The inorganic base is selected from the group comprising of alkali earth metal carbonates or hydroxides.
The alkali earth metal hydroxides are selected from the group comprising of sodium hydroxide, potassium hydroxide and lithium hydroxide.
The alkali earth metal carbonates are selected form the group comprising of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate etc but preferably potassium carbonate.
The organic solvent is selected from the group comprising of dimethyl formamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane etc, but preferably dimethyl formamide. The reaction mixture was stirred at 0 to 5°C.
N-halosuccinimide selected from the group comprising of N-bromosuccinimide, N-chlorosuccuiimide but preferably N-chlorosuccinimide was added to the mixture followed by the addition of an organic base selected from the group comprising of triethyl amine, diisopropyl amine, diisopropylethyl amine, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) but preferably, 1,8-Diazabicyclo (5.4.0) undec-7-ene (DBU).

The reaction mixture was stirred at 0 to 30°C till completion of reaction and then quenched with water. The reaction mixture was extracted with an aromatic hydrocarbon like toluene and the organic layer was then concentrated under reduced pressure to give compound of formula (III).
The present inventors found that for ensuring completion of the reaction, a mixture of an inorganic base and an organic base, were required which needed to be added separately.
The present inventors found that for ensuring completion of the reaction, the quantity of DBU required is in the range of 1.1 to 2.0 moles equivalent per mole of compound of formula (II) and preferably between 1.2 and 1.75 moles equivalent per mole of compound of formula (II).
The compound of formula (III) thus obtained is racemized to the corresponding mixture dl-erythro-threo mixture in the presence of hydrogenating catalyst. The catalyst used for hydrogenation of the compound of formula (III) is selected form palladium-carbon, platinum-carbon etc, but preferably palladium-carbon with an alcohol as the solvent.
The alcohol is selected from the group comprising of methanol, ethanol, propanol, isopropanol, preferably methanol.
The dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide of formula (IV) thus formed was then treated with a base to provide dl-threo-2-phenyl-2-piperidyl-2-acetamide (V).
The base was selected from the group comprising of sodium methoxide, sodium ethoxide, potassium tert-butoxide etc but preferably potassium tert-butoxide.
The reaction is carried out in a solvent which is selected from a group comprising of aromatic hydrocarbons such as toluene, xylene and alcohols such as ethanol, tert-butanol etc.

The reaction is carried out at 65 to 85°C, but preferably between 70 and 75°C. After completion of the reaction, the reaction mixture is cooled to ambient temperature and neutralized followed by stirring at an alkaline pH to get the dl-threo isomer of formula (V).
The dl-threo-2-phenyl-2-piperidyl-2-acetamide (V) isomer was resolved using dibenzoyl-D-tartaric acid in isopropyl alcohol to give d-threo-2-phenyl-2-piperidyl-2-acetamide (VI) which on subsequent treatment with methanol and sulphuric acid gave dexmethylphenidate of formula (I).
During resolution step the undesired isomer l-threo-2-phenyl-2-piperidyl-2-acetamide (II) which remains in mother liquor along with uncrystallized d-threo isomer (VI) is converted into dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (IV) as disclosed in Scheme-I, thereby making the process cost effective and commercially viable by a simple and a convenient method.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.

EXAMPLES:
Example 1:
Preparation of 2-phenyl-2-piperidin-2-ylideneacetamide (III):
A mixture l-threo-2-phenyl-2-piperidyl-2-acetamide (II) (containing -15% of d-threo
amide, 0.500 Kg, 2.31 moles) and dimethylformamide (3.0 litres) was cooled between
0 and 5°C. Potassium carbonate (0.100 Kg, 0.720 moles) was added and after 0.5 hours, N-chlorosuccinimide (0.428 Kg, 3.20 moles) and 1,8-Diazabicyclo [5.4.0] undec-7-ene (0.439 Kg, 2.88 moles) were added. The reaction was stirred at 0 to 5°C
till completion of reaction. The reaction mass was cooled to 0 to 5°C and diluted with
DM water (2.5 litres). Toluene (2.5 litres) was introduced and stirred for 1 hour. The
organic layer was concentrated under reduced pressure to give a yield of 0.406 Kg
(Yield 82%) of formula (HI), Purity: > 98%.
Melting point: 132-134°C;
IR (KBr): 3481, 3294,2956, 1634, 1568, and 1339 cm"1;
MS (m/z): 172, 200,217, 239, 344, 455;
'H NMR(DMSCM6): 5 = 1.4-1.5(m, 2H) 1.50-1.60 (m, 2 H), 1.80-1.90 (t, 2 H), 3.1-3.2
(t, 2 H), 4.5-5.0 (s, 1H), 5.8-6.2 (s, 1H), 7.0-7.5 (m, 5 H), 10.3 (s, 1H);
13C NMR (100 MHz, DMSO) 6 = 20.27, 22.51, 27.83, 41.12, 96.41, 127.42, 129.59,
132.95, 139.28,158.61,172.68.
Example 2:
Preparation of dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (TV)
2-Phenyl-2-piperidin-2-ylideneacetamide (III) (0.400 kg, 1.85 moles), 10% Pd-C (40 g) in methanol (4.0 litres) were hydrogenated at 10.0 kg/cm2 pressure at 45°C for 10 hour. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to 30°C and filtered through hyflow supercel. The filtrate was concentrated under reduced pressure. Acetic acid (2.9 litres) was added to the reaction mass, stirred for 30 minutes at 60°C and concentrated under reduced pressure. Ethyl acetate (1.45 litres) was added to the concentrated mass and cooled to 0 to 5°C. The solid was filtered,

washed with cold ethyl acetate (0.37 litres) and dried, to give a yield of 0.32 Kg (Yield
79.5%), Purity: > 98%.
Melting point: 140-143°C;
IR(KBr): 3313, 3037,2966, 2928, 2766, 1670, 1409, 1361, 1024 cm-1;
MS (m/z): 219, 239, 241, 455;
dl-erythro: dl-threo content by HPLC (%) 99.72:0.28.
Example 3:
Preparation of dl-threo-2-phenyl-2-piperidyl-2-acetamide (V)
The dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (IV) (0.31 Kg, 1.42 moles),
potassium tert-butoxide (0.426 Kg, 3.79 moles) and toluene (7.75 litres) were heated at
70 to 75°C for 24 hours. After completion of the reaction as monitored by TLC, the
reaction mixture was cooled between 20 and 25°C and dilute hydrochloric acid solution
was added and further stirred for 1 hour. The aqueous layer was separated, basified to
pH 12.5 using 30% sodium hydroxide solution. The solid obtained was filtered, washed
with DM water and dried to give a yield of 0.25 Kg (Yield 81%) of formula (V), Purity:
> 98%.
Melting point: 173-175°C;
IR(KBr): 3283, 3035,2951,2931,1679, 1397, 1360, 1031 cm'1;
MS (m/z): 136,219,221,241,437,473;
1H NMR (CD3OD): 5 0.9-1.3(m, 3H) 1.40-1.70 (m, 3H), 2.60-2.70 (d, 1 H), 3.0-3.1 (d,
1 H), 3.1-3.2 (d, 1 H), 3.3-3.4 (d, 1H), 7.2-7.4 (m, 5 H);
dl-erythro: dl-threo content by HPLC (%) 0.60: 99.40,
d-threo: 1-threo content by chiral HPLC (%) 50.34:49.66.

CLAIMS:
1. A process for preparation of dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (IV) comprising reaction of l-threo-2-phenyl-2-piperidyl-2-acetamide with an inorganic base followed by treatment with N-halosuccinimide and an organic base in a solvent and subsequent hydrogenation in a second organic solvent to give dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (IV).
2. A process as claimed in claim 1, wherein the inorganic base is selected from the group comprising of alkali earth metal hydroxides and alkali earth metal carbonates.
3. A process as claimed in claim 2, wherein the inorganic base is preferably an alkali earth metal carbonate selected form the group comprising of sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate.
4. The process as claimed in claim 1, wherein the N-halosuccinimide is selected from group comprising of N-chlorosuccinimide, N-bromosuccinirnide but preferably N-chlorosuccinimide.
5. The process as claimed in claim 1, wherein the organic base is selected form group comprising of diisopropyl amine, diisopropylethyl amine, triethyl amine, 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), but preferably 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU).
6. The process as claimed in claim 5, wherein DBU is employed in the range of 1.1 to 2.0 moles but preferably between 1.2 and 1.75 moles per mole of compound of formula (II).
7. The process as claimed in claim 1, wherein the solvent is selected from the group comprising of dimethylformamide, dimethylsulfoxide, N-

methylpyrrolidone, tetrahydrofuran 1,4-dioxane but preferably
dimethylformamide.
8. The process as claimed in claim 1, wherein hydrogenation is carried out in a second organic solvent selected from group comprising of alcohols and hydrocarbons.
9. 2-PhenyI-2-piperidin-2-ylideneacetamide,

10. A process for preparing dexmethylphenidate of formula (I) comprising,
a. treatment of l-threo-2-phenyl-2-piperidyl-2-acetamide (H) with an
inorganic base followed by reaction with a N-halosuccinimide in presence
of an organic base in a solvent to give compound of formula (III),
b. hydrogenation of compound of formula (III) in a second organic solvent to
give dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (IV),
c. reaction of dl-erythro-threo-2-phenyl-2-piperidyl-2-acetamide (IV) with
potassium tert-butoxide in toluene to give dl-threo-2-phenyl-2-piperidyl-2-
acetamide (V);
d. resolving dl-threo-2-phenyl-2-piperidyl-2-acetamide (V) using dibenzoyl-
D-tartaric acid in isopropyl alcohol to give d-threo-2-phenyl-2-piperidyl-
2-acetamide (VI);
e. treating d-threo-2-phenyl-2-piperidyl-2-acetamide (VI) with methanol and
sulphuric acid to give dexmethylphenidate of formula (I).

Documents

Name Date
2378-mum-2009-form 2(12-10-2009).doc 2009-10-12
2378-mum-2009-claims (12-10-2009).doc 2009-10-12
2378-mum-2009-abstract(12-10-2009).doc 2009-10-12
2378-MUM-2009-FORM 2(TITLE PAGE)-(12-10-2010).pdf 2010-10-12
2378-MUM-2009-FORM 5(12-10-2010).pdf 2010-10-12
2378-MUM-2009-FORM 3(12-10-2010).pdf 2010-10-12
2378-mum-2009-form 2(12-10-2010).pdf 2010-10-12
2378-MUM-2009-FORM 1(12-10-2010).pdf 2010-10-12
2378-MUM-2009-CORRESPONDENCE(12-10-2010).pdf 2010-10-12
2378-MUM-2009-ABSTRACT(12-10-2010).pdf 2010-10-12
2378-MUM-2009-CLAIMS(12-10-2010).pdf 2010-10-12
2378-MUM-2009-DESCRIPTION(COMPLETE)-(12-10-2010).pdf 2010-10-12
2378-MUM-2009-FER_SER_REPLY [13-01-2018(online)].pdf 2018-01-13
2378-mum-2009-form 3.pdf 2018-08-10
2378-MUM-2009-PatentCertificate30-03-2018.pdf 2018-03-30
2378-MUM-2009-IntimationOfGrant30-03-2018.pdf 2018-03-30
2378-mum-2009-form 2(title page).pdf 2018-08-10
2378-MUM-2009-FORM 18(6-3-2013).pdf 2018-08-10
2378-mum-2009-form 2.pdf 2018-08-10
2378-mum-2009-form 1.pdf 2018-08-10
2378-MUM-2009-OTHERS [13-01-2018(online)].pdf 2018-01-13
2378-MUM-2009-FER.pdf 2018-08-10
2378-mum-2009-correspondence.pdf 2018-08-10
2378-mum-2009-description(provisional).pdf 2018-08-10
2378-MUM-2009-CORRESPONDENCE(6-3-2013).pdf 2018-08-10
2378-MUM-2009-RELEVANT DOCUMENTS [28-03-2019(online)].pdf 2019-03-28

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