WO1998025902A1 - The preparation of enantiomerically-enriched threo-methylphenidate - Google Patents

The preparation of enantiomerically-enriched threo-methylphenidate Download PDF

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Publication number
WO1998025902A1
WO1998025902A1 PCT/GB1997/003418 GB9703418W WO9825902A1 WO 1998025902 A1 WO1998025902 A1 WO 1998025902A1 GB 9703418 W GB9703418 W GB 9703418W WO 9825902 A1 WO9825902 A1 WO 9825902A1
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WO
WIPO (PCT)
Prior art keywords
process according
methylphenidate
acid
crystallisation
threo
Prior art date
Application number
PCT/GB1997/003418
Other languages
English (en)
French (fr)
Inventor
Susan Faulconbridge
Hooshang Shahriari Zavareh
Graham Robert Evans
Marianne Langston
Original Assignee
Medeva Europe Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9625972.6A external-priority patent/GB9625972D0/en
Priority claimed from GBGB9712298.0A external-priority patent/GB9712298D0/en
Application filed by Medeva Europe Limited filed Critical Medeva Europe Limited
Priority to PL97334136A priority Critical patent/PL334136A1/xx
Priority to JP52637898A priority patent/JP2001506621A/ja
Priority to HU0001604A priority patent/HUP0001604A3/hu
Priority to AU78470/98A priority patent/AU7847098A/en
Priority to EP97949034A priority patent/EP0948484A1/en
Priority to CA002272373A priority patent/CA2272373A1/en
Publication of WO1998025902A1 publication Critical patent/WO1998025902A1/en
Priority to NO992875A priority patent/NO992875L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to processes for the preparation of enantiomerically-enriched f ⁇ re ⁇ -methylphenidate, and in particular to bioresolution, to the separation of the enantiomers of acid addition salt forms of tAre ⁇ -methylphenidate, and to the enhancement of enantiomeric excess (ee) of one enantiomer in a mixture.
  • Methylphenidate is a therapeutic agent that is widely used in the treatment of attention-deficient hyperactivity disorder. It is a controlled substance.
  • Methylphenidate was first prepared as a mixture of the erythro and threo racemates.
  • US-A-2957880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo disastereoisomer. It is now considered that it is the d-threo [or (R,R)) enantiomer that has the preferred therapeutic activity. Uses of this enantiomer are disclosed in WO-A-9703671, WO-A-9703672 and WO-A-9703673, the contents of which are incorporated herein by reference.
  • WO-A-9727176 and WO-A-9732851 disclose that the resolution of methylphenidate has also been achieved, more economically, using either O,O '- diaroyltartaric acids or menthoxyacetic acid. These resolutions provide d-threo- methylphenidate in high ee and chemical purity, e.g. containing less than 2% w/w of resolving agent and/or ritalinic acid.
  • racemate and single enantiomers of a salt of a chiral compound such as t ⁇ reo-methylphenidate have different solid-state crystalline forms.
  • Such a salt will have an enantiomeric composition which corresponds to its point of maximum solubility (the eutectic composition), and this is dependent upon the solubility of the racemic salt and the single enantiomer salt.
  • the solubility ratio ⁇ is given by the ratio of the solubility of the racemate salt divided by the solubility of the single enantiomer salt.
  • One aspect of the present invention is based upon the discovery that certain crystalline salts of t/re ⁇ -methylphenidate, wherein the counterion is achiral, allow for the enhancement of enantiomeric excess (ee) by recrystallisation/crystallisation of partially enriched material in a suitable solvent.
  • certain salts of the single enantiomer showed much lower solubility than the corresponding racemate in methanol/TBME (tert-butyl methyl ether).
  • a second aspect of the present invention is based on the discovery that (R,R)- methylphenidate (1) can be conveniently obtained by means of biocatalytic resolution of a racemic compound of formula 2 (of which one enantomer is shown, for convenience), using a range of hydrolase enzymes.
  • crystallisation can be used to give essentially enantiopure t ⁇ re ⁇ -methylphenidate.
  • the starting material should be enantiomerically enriched above the eutectic point of the t ⁇ reo-methylphenidate salt.
  • the eutectic point has been measured to be 25% ee by solubility. That is to say, t//reo-methylphenidate.HCl salt with a composition of enantiomers greater than 25% ee will, by crystallisation, yield enriched material.
  • tAre ⁇ -methylphenidate salts of significantly lower enantiomeric purity in the range 25-95%, preferably 50-95%, and more preferably 70-95%, can be usefully enriched by direct crystallisation.
  • the process of the invention is therefore of considerable utility with a feedstock of t ireo-methylphenidate of moderate enantiomeric purity, for example following classical resolution.
  • Any resolving agent that may be present can be removed, e.g. to a level of 2% w/w or below, e.g. no more than 0.5 or 1% w/w.
  • the novel crystallisation process can be used in combination with the novel biocatalytic resolution.
  • the novel bioresolution encompasses the following embodiments:
  • bioresolution process of the present invention provides a number of benefits, including mild reaction conditions (ambient temperature, low environmental impact), cost savings by avoidance of stoichiometric resolving agents, and easier processing (e.g. simple solvent partitioning in selected cases instead of salt cracking).
  • suitable biocatalysts can readily be identified. It is preferred that the biocatalyst provides a sufficient degree of optical enrichment that the desired product can be used effectively, e.g. at least 20%, preferably at least 40% , and more preferably at least 50% , ee, up to substantially single enantiomer product, e.g. at least 80% or 90% ee.
  • novel crystallisation process is also useful to enhance the ee of material of high ee, e.g. at least 95% ee, if that has been produced in chemically-pure form, using a more efficient resolving agent for this purpose than l, -binaphthyl-2,2'-diyl hydrogen phosphate.
  • a more efficient resolving agent for this purpose than l, -binaphthyl-2,2'-diyl hydrogen phosphate.
  • the solvent that is used in the invention can readily be chosen by those of ordinary skill in the art.
  • the solvent should be sufficiently polar, e.g. an alcohol, optionally together with another solvent such as an ether.
  • An aprotic solvent such as acetonitrile or acetone can also be used.
  • a mixture of methanol and TBME is preferred.
  • the salt used in the invention may have the formula
  • HX is any achiral acid that forms a suitable salt.
  • the suitability of any salt for use in the invention is readily tested in a crystallisation procedure by one of ordinary skill in the art.
  • HX is preferably a hydrohalide, and X is more preferably Br or Cl.
  • racemic £ /-t »reo-methylphenidate.HCl (1.0 g) was suspended in 10 ml of 1 : 1 methanol:TBME (7.4 g) and stirred at 25°C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE. This gave 0.640 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.340 g of a white solid. i//-t ⁇ reo-methylphenidate.HCl therefore has a solubility of 34 mg per ml of 1 : 1 MeOH:TBME at 25°C.
  • the enrichment procedure may also be effected by simply treating a solution of //weo-methylphenidate free base above the eutectic point (>25% ee) with hydrogen chloride in methanol, and isolating the resultant precipitate.
  • Table 2 The results of a series of experiments are given in Table 2.
  • Example 1 95% - d-threo 99.0% (90%) 36.5% (6%) The following Examples illustrate the present invention more specifically.
  • Example 1 95% - d-threo 99.0% (90%) 36.5% (6%)
  • Suitable enzymes for the bioresolution were identified by the following screening protocol: 100 mg of racemic tftre ⁇ -methylphenidate (free base) was dissolved in 100 mM phosphate buffer adjusted to pH 7. Approximately 50 mg (or equivalent ml) of each candidate enzyme was added and the reactions incubated at 30 °C for 24 hours with gentle agitation. For assaying purposes, 40 ⁇ l of the reaction mixture was dispensed into a vial and allowed to evaporate over KOH in a desiccator overnight. The residue was then dissolved in 1 ml IPA/2% diethylamine solution and undissolved material removed by centrifugation.
  • the reaction mixture was then heated at reflux for 5 minutes. After this 30 ml TMBE was added to the reaction mixture which was cooled over one hour to room temperature, and finally at 0°C for 1 hour. The solid material was collected by filtration, washing the reaction vessel with 30 ml TMBE. This gave 13.50 g (77.8%) of solid precipitate, with an enantiomeric excess of 97.8%. The mother liquors were evaporated to dryness to give 3.60 g of a yellow/orange solid (20.7%), with an enantiomeric excess of 32.1%.
  • Example 7 ⁇ i-t 7reo-methylphenidate enriched in the ./-enantiomer (91.3% ee) 11.50 g was taken up in 23 ml of methanol, and stirred at 40-50°C whilst bubbling hydrogen chloride gas through the reaction mixture for 10 minutes. The reaction mixture was then heated at reflux for 5 minutes. After this 23 ml TMBE was added to the reaction mixture which was cooled over one hour to room temperature, and finally at 0°C for 1 hour. The solid material was collected by filtration, washing the reaction vessel with 23 ml TMBE. This gave 10.60 g (79.7%) of solid precipitate, with an enantiomeric excess of 99.2%. The mother liquors were evaporated to dryness to give 2.50 g of a white solid (18.8%), with an enantiomeric excess of 43.6%.
  • the resultant racemic i//-tAre ⁇ -methylphenidate.HBr (0.500 g) was suspended in 5 ml of 1: 1 methanol:TBME (3.80 g) and stirred at 25°C for 16 hours. The solid material was collected by filtration. This gave 0.355 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.140 g of a white solid. /-t/7re ⁇ -methylphenidate.HBr therefore has a solubility of 28 mg per ml of 1 : 1 MeOH:TBME at 25°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
PCT/GB1997/003418 1996-12-13 1997-12-11 The preparation of enantiomerically-enriched threo-methylphenidate WO1998025902A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PL97334136A PL334136A1 (en) 1996-12-13 1997-12-11 Method of obtaining enantiomerically enriched methyl threophenidate
JP52637898A JP2001506621A (ja) 1996-12-13 1997-12-11 エナンチオマー濃縮されたトレオ−メチルフェニデートの調製法
HU0001604A HUP0001604A3 (en) 1996-12-13 1997-12-11 The preparation of an enantiomerically-enriched threo-methylphenidate
AU78470/98A AU7847098A (en) 1996-12-13 1997-12-11 The preparation of enantiomerically-enriched threo- methylphenidate
EP97949034A EP0948484A1 (en) 1996-12-13 1997-12-11 The preparation of enantiomerically-enriched threo-methylphenidate
CA002272373A CA2272373A1 (en) 1996-12-13 1997-12-11 The preparation of enantiomerically-enriched threo-methylphenidate
NO992875A NO992875L (no) 1996-12-13 1999-06-11 Fremstilling av enantiomert anriket threo-metylfenidat

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9625972.6A GB9625972D0 (en) 1996-12-13 1996-12-13 Bioresolution
GB9712298.0 1997-06-12
GB9625972.6 1997-06-12
GBGB9712298.0A GB9712298D0 (en) 1997-06-12 1997-06-12 Crystallisation

Publications (1)

Publication Number Publication Date
WO1998025902A1 true WO1998025902A1 (en) 1998-06-18

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PCT/GB1997/003418 WO1998025902A1 (en) 1996-12-13 1997-12-11 The preparation of enantiomerically-enriched threo-methylphenidate

Country Status (9)

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EP (1) EP0948484A1 (cs)
JP (1) JP2001506621A (cs)
AU (1) AU7847098A (cs)
CA (1) CA2272373A1 (cs)
CZ (1) CZ206299A3 (cs)
HU (1) HUP0001604A3 (cs)
NO (1) NO992875L (cs)
PL (1) PL334136A1 (cs)
WO (1) WO1998025902A1 (cs)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6025502A (en) * 1999-03-19 2000-02-15 The Trustees Of The University Of Pennsylvania Enantopselective synthesis of methyl phenidate
US6100401A (en) * 1998-04-20 2000-08-08 Novartris Ag Process for preparing the d-threo isomer of methylphenidate hydrochloride
US6127385A (en) * 1999-03-04 2000-10-03 Pharmaquest Limited Method of treating depression using l-threo-methylphenidate
US6162919A (en) * 1998-12-03 2000-12-19 Novartis Ag Process for preparing the d-threo isomer of methylphenidate hydrochloride
EP1163907A1 (en) * 2000-06-17 2001-12-19 Pharmaquest Limited Use of l-threo-methylphenidate for the treatment of depression
US6395752B1 (en) * 1999-03-04 2002-05-28 Pharmaquest Limited Method of treating depression using 1-threo-methylphenidate
EP1292305A4 (en) * 2000-04-12 2004-04-07 Mclean Hospital Corp METHOD FOR INHIBITING DOPAMINE USING L-THREO-METHYLPHENIDATE
WO2004080959A3 (en) * 2003-03-07 2004-11-25 Isp Investments Inc Process for the preparation of dexmethylphenidate hydrochloride
US7115631B2 (en) 1995-12-04 2006-10-03 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US7431944B2 (en) 1995-12-04 2008-10-07 Celgene Corporation Delivery of multiple doses of medications
US7459560B2 (en) 1997-05-22 2008-12-02 Celgene Corporation Processes and intermediates for resolving piperidyl acetamide stereoisomers
US7897777B2 (en) 2007-01-05 2011-03-01 Archimica, Inc. Process of enantiomeric resolution of D,L-(±)-threo-methylphenidate
WO2012080834A1 (en) 2010-12-17 2012-06-21 Rhodes Technologies Low-temperature synthesis of methylphenidate hydrochloride
US8552030B2 (en) 2009-05-07 2013-10-08 Malladi Drugs & Pharmaceuticals Ltd. Process for the preparation of d-threo-ritalinic acid hydrochloride by resolution of dl-threo-ritalinic acid using chiral carboxylic acid
US8916588B2 (en) 2011-03-23 2014-12-23 Ironshore Pharmaceuticals & Development, Inc. Methods for treatment of attention deficit hyperactivity disorder
US8927010B2 (en) 2011-03-23 2015-01-06 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9028868B2 (en) 2011-03-23 2015-05-12 Ironshore Pharmaceuticals & Development, Inc. Methods and compositions for treatment of attention deficit disorder
US9119809B2 (en) 2011-03-23 2015-09-01 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9233924B2 (en) 2014-03-11 2016-01-12 Ampac Fine Chemicals Llc Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof
US9283214B2 (en) 2011-03-23 2016-03-15 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9498447B2 (en) 2011-03-23 2016-11-22 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9603809B2 (en) 2011-03-23 2017-03-28 Ironshore Pharmaceuticals & Development, Inc. Methods of treatment of attention deficit hyperactivity disorder
US10081597B2 (en) 2014-06-27 2018-09-25 Embio Limited Process for preparation of dexmethylphenidate hydrochloride
US10292937B2 (en) 2011-03-23 2019-05-21 Ironshore Pharmaceuticals & Development, Inc. Methods of treatment of attention deficit hyperactivity disorder
US10905652B2 (en) 2011-03-23 2021-02-02 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US11241391B2 (en) 2011-03-23 2022-02-08 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder

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Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115631B2 (en) 1995-12-04 2006-10-03 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US7431944B2 (en) 1995-12-04 2008-10-07 Celgene Corporation Delivery of multiple doses of medications
US7459560B2 (en) 1997-05-22 2008-12-02 Celgene Corporation Processes and intermediates for resolving piperidyl acetamide stereoisomers
US6100401A (en) * 1998-04-20 2000-08-08 Novartris Ag Process for preparing the d-threo isomer of methylphenidate hydrochloride
US6162919A (en) * 1998-12-03 2000-12-19 Novartis Ag Process for preparing the d-threo isomer of methylphenidate hydrochloride
US6395752B1 (en) * 1999-03-04 2002-05-28 Pharmaquest Limited Method of treating depression using 1-threo-methylphenidate
US6127385A (en) * 1999-03-04 2000-10-03 Pharmaquest Limited Method of treating depression using l-threo-methylphenidate
US6025502A (en) * 1999-03-19 2000-02-15 The Trustees Of The University Of Pennsylvania Enantopselective synthesis of methyl phenidate
EP1292305A4 (en) * 2000-04-12 2004-04-07 Mclean Hospital Corp METHOD FOR INHIBITING DOPAMINE USING L-THREO-METHYLPHENIDATE
EP1163907A1 (en) * 2000-06-17 2001-12-19 Pharmaquest Limited Use of l-threo-methylphenidate for the treatment of depression
WO2004080959A3 (en) * 2003-03-07 2004-11-25 Isp Investments Inc Process for the preparation of dexmethylphenidate hydrochloride
US7897777B2 (en) 2007-01-05 2011-03-01 Archimica, Inc. Process of enantiomeric resolution of D,L-(±)-threo-methylphenidate
US8552030B2 (en) 2009-05-07 2013-10-08 Malladi Drugs & Pharmaceuticals Ltd. Process for the preparation of d-threo-ritalinic acid hydrochloride by resolution of dl-threo-ritalinic acid using chiral carboxylic acid
EP2937336A1 (en) 2010-12-17 2015-10-28 Rhodes Technologies Low-temperature synthesis of methylphenidate hydrochloride
WO2012080834A1 (en) 2010-12-17 2012-06-21 Rhodes Technologies Low-temperature synthesis of methylphenidate hydrochloride
US9475770B2 (en) 2010-12-17 2016-10-25 Rhodes Technologies Low-temperature synthesis of methylphenidate hydrochloride
US10617651B2 (en) 2011-03-23 2020-04-14 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US11241391B2 (en) 2011-03-23 2022-02-08 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9034902B2 (en) 2011-03-23 2015-05-19 Ironshore Pharmaceuticals & Development, Inc. Methods for treatment of attention deficit hyperactivity disorder
US9119809B2 (en) 2011-03-23 2015-09-01 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9023389B1 (en) 2011-03-23 2015-05-05 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US12383506B2 (en) 2011-03-23 2025-08-12 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9283214B2 (en) 2011-03-23 2016-03-15 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9289394B2 (en) 2011-03-23 2016-03-22 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US8927010B2 (en) 2011-03-23 2015-01-06 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9498447B2 (en) 2011-03-23 2016-11-22 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9511032B2 (en) 2011-03-23 2016-12-06 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US11911518B2 (en) 2011-03-23 2024-02-27 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9028868B2 (en) 2011-03-23 2015-05-12 Ironshore Pharmaceuticals & Development, Inc. Methods and compositions for treatment of attention deficit disorder
US9603809B2 (en) 2011-03-23 2017-03-28 Ironshore Pharmaceuticals & Development, Inc. Methods of treatment of attention deficit hyperactivity disorder
US10292937B2 (en) 2011-03-23 2019-05-21 Ironshore Pharmaceuticals & Development, Inc. Methods of treatment of attention deficit hyperactivity disorder
US11241392B2 (en) 2011-03-23 2022-02-08 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US10179108B2 (en) 2011-03-23 2019-01-15 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US10182995B2 (en) 2011-03-23 2019-01-22 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9889095B2 (en) 2011-03-23 2018-02-13 Ironshore Pharmaceuticals & Development, Inc. Methods for treatment of attention deficit hyperactivity disorder
US8916588B2 (en) 2011-03-23 2014-12-23 Ironshore Pharmaceuticals & Development, Inc. Methods for treatment of attention deficit hyperactivity disorder
US10881618B2 (en) 2011-03-23 2021-01-05 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US10905652B2 (en) 2011-03-23 2021-02-02 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9603808B2 (en) 2011-03-23 2017-03-28 Ironshore Pharmaceuticals & Development, Inc. Method of treatment of attention deficit hyperactivity disorder
US9573896B2 (en) 2014-03-11 2017-02-21 Ampac Fine Chemicals Llc Methods for preparing d-threo-methylphenidate using diazomethane, and compositions thereof
US9233924B2 (en) 2014-03-11 2016-01-12 Ampac Fine Chemicals Llc Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof
US10081597B2 (en) 2014-06-27 2018-09-25 Embio Limited Process for preparation of dexmethylphenidate hydrochloride

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Publication number Publication date
NO992875D0 (no) 1999-06-11
CZ206299A3 (cs) 1999-09-15
NO992875L (no) 1999-06-14
AU7847098A (en) 1998-07-03
HUP0001604A2 (hu) 2000-10-28
EP0948484A1 (en) 1999-10-13
PL334136A1 (en) 2000-02-14
CA2272373A1 (en) 1998-06-18
HUP0001604A3 (en) 2003-03-28
JP2001506621A (ja) 2001-05-22

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