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WO2003031411A2 - Dedoublement direct de chlorhydrate de threo-methylphenidate racemique - Google Patents

Dedoublement direct de chlorhydrate de threo-methylphenidate racemique Download PDF

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Publication number
WO2003031411A2
WO2003031411A2 PCT/US2002/032658 US0232658W WO03031411A2 WO 2003031411 A2 WO2003031411 A2 WO 2003031411A2 US 0232658 W US0232658 W US 0232658W WO 03031411 A2 WO03031411 A2 WO 03031411A2
Authority
WO
WIPO (PCT)
Prior art keywords
zreo
methylphenidate
toluoyl
mixture
salt
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2002/032658
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English (en)
Other versions
WO2003031411A3 (fr
Inventor
Jeroen Verheijen
Shoucheng Du
Mel H. Epstein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sention Inc
Original Assignee
Sention Inc
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
Application filed by Sention Inc filed Critical Sention Inc
Priority to AU2002353803A priority Critical patent/AU2002353803A1/en
Publication of WO2003031411A2 publication Critical patent/WO2003031411A2/fr
Publication of WO2003031411A3 publication Critical patent/WO2003031411A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

  • Methylphenidate is a mild CNS stimulant.
  • Racemic t zreo-methylphenidate hydrochloride 1 is currently marketed as a pharmaceutical agent that is widely used for the treatment of children with Attention Deficit Disorder (ADD) and/or Attention Deficit and Hyperactivity Disorder (ADHD). It has been shown that the pharmaceutical activity for this indication is mainly attributable to the -(2R,2'R)- empo enantiomer 2.
  • the /-(2S,2'S)- threo enantiomer 3 of methylphenidate hydrochloride may have some attractive pharmaceutical applications for the treatment of depression in terminally ill patients, and for treatment of manic, psychotic and anxiety disorders. Accordingly, there is a need for economical and practical processes for the direct resolution of racemic t zreo-methylphenidate hydrochloride.
  • the present invention relates to an improved direct resolution of racemic t zreo-methylphenidate hydrochloride.
  • the invention describes a three- step process for resolving racemic t/zreo-methylphenidate hydrochloride to either of its enantiomers using the single enantiomers of O, O '-di-p-toluoyltartaric acid.
  • the subject invention provides a method for the isolation of d-t zreo-methylphenidate hydrochloride from its racemic hydrochloride salt mixture comprising the steps of:
  • reaction solvent mixture 1) heating a reaction mixture of racemic t zreo-methylphenidate hydrochloride, di- ?-toluoyl-D-tartaric acid and base in a minimum amount of an initial inert reaction solvent, followed by addition of water to form a final reaction solvent mixture;
  • step 2 2) cooling the reaction mixture of step 1 to crystallize an enantiomerically enriched ti-t/zreo-methylphenidate di-p-toluoyl-D- tartrate salt and further reacting the tartrate salt with aqueous base;
  • the subject invention provides a method for the isolation of /-t/zreo-methylphenidate hydrochloride from its racemic hydrochloride salt mixture comprising the steps of:
  • reaction solvent mixture 1) heating a reaction mixture of racemic t/zreo-methylphenidate hydrochloride, di-p-toluoyl-L-tartaric acid and base in a minimum amount of an initial inert reaction solvent, followed by addition of water to form a final reaction solvent mixture;
  • step 2 2) cooling the reaction mixture of step 1 to crystallize an enantiomerically enriched /-t/zreo-methylphenidate di-p-toluoyl-L- tartrate salt and further reacting the tartrate salt with aqueous base;
  • the reaction mixture in the first step of the isolation of either enantiomer, is heated in an inert reaction solvent comprising a solvent system selected from lower alkanols, ethers, acetonitrile or ketonss or a miscible or immiscible aqueous mixture thereof.
  • the inert reaction solvent is methanol, wherein after addition of water the reaction solvent comprises a methanohwater mixture in a range from 1 : 1 to 2: 1.
  • the amount of either enantiomer of di-p- toluoyltartaric acid used is at least 1 equivalent, at least 0.75 equivalent or even at least 0.5 equivalent of the amount of racemic t/zreo-methylphenidate.
  • the base used in the reaction mixture of step 1 may be a substituted or unsubstituted morpholine, an alkali metal hydroxide, or a tri- lower alkyl amine.
  • the base may comprise a basic reagem selected from 4-methylmorpholine, sodium hydroxide, potassium hydroxide, trimethylamine, or triethylamine.
  • the enantiomeric enrichment achieved by the subject invention, for the isolation of either enantiomer of t/zreo-methylphenidate hydrochloride is 90%, 95%, 99% or even 99.5%.
  • the aqueous base, in step 2 of the isolation of either enantiomer of t zreo-methylphenidate is selected from ammonium hydroxide, sodium hydroxide or potassium hydroxide.
  • step 3 of the isolation of either enantiomer of t/zreo- methylphenidate converts the single enantiomer of t/zreo-methylphenidate into a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the present invention relates to an improved direct resolution of racemic t/zreo-methylphenidate hydrochloride.
  • the invention describes a three- step process for resolving racemic t/zreo-methylphenidate hydrochloride to either of its enantiomers using single enantiomers of O, O '-di-p-toluoyltartaric acid.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • Enantiomeric excess (ee) is the "excess" of one enantiomer over the other.
  • the enantiomeric excess would be zero (0% ee).
  • the enantiomeric excess would be 90% ee (95% -5% (the amount of the enriched enantiomer minus the amount of the other enantiomer)).
  • higher enantiomeric purity >about 50% ee
  • enantiomeric excess is preferred with enantiomeric excess of between about 75% ee and about 90% ee being more preferred and enantiomeric excess of greater than about 90% ee being particularly preferred.
  • salts refers to the relatively nontoxic inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in silu during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphonate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts of the compounds, e.g. from nontoxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic,
  • the subject invention provides a method for the isolation of d-t/zreo-methylphenidate hydrochloride from its racemic hydrochloride salt mixture comprising the steps of:
  • reaction solvent mixture 1) heating a reaction mixture of racemic t/zreo-methylphenidate hydrochloride, di-p-toluoyl-D-tartaric acid and base in a minimum amount of an initial inert reaction solvent, followed by addition of water to form a final reaction solvent mixture;
  • step 2 2) cooling the reaction mixture of step 1 to crystallize an enantiomerically enriched -t/zreo-methylphenidate di-p-toluoyl-D- tartrate salt and further reacting the tartrate salt with aqueous base;
  • the subject invention provides a method for the isolation of /-t/zreo-methylphenidate hydrochloride from its racemic hydrochloride salt mixture comprising the steps of:
  • step 1 1) heating a reaction mixture of racemic t/zreo-methylphenidate hydrochloride, di-p-toluoyl-L-tartaric acid and base in a minimum amount of an initial inert reaction solvent, followed by addition of water to form a final reaction solvent mixture; 2) cooling the reaction mixture of step 1 to crystallize an enantiomerically enriched /-t zreo-methylphenidate di-p-toluoyl-L- tartrate salt and further reacting the tartrate salt with aqueous base; and
  • the reaction mixture in the first step of the isolation of either enantiomer, is refluxed in an inert reaction solvent comprising a solvent system selected from lower alkanols, ethers, acetonitrile or ketones or a miscible or immiscible aqueous mixture thereof.
  • the inert reaction solvent is methanol, wherein after addition of water the reaction solvent comprises a methanokwater mixture in a range from 1 :1 to 2: 1.
  • the amount of single enantiomer of di-p- toluoyltartaric acid used is at least 1 equivalent, at least 0.75 equivalent or even at least 0.5 equivalent of the amount of racemic t/zreo-methylphenidate.
  • step 1 of the isolation of either enantiomer of t/zreo-methylphenidate single enantiomers of di-o-toluoyltartaric acid or di-m- toluoyltartaric acid can be used instead of single enantiomers of di-p-toluoyltartaric acid.
  • the base used in the reaction mixture of step 1 of the isolation of either enantiomer of t zreo-methylphenidate may be a substituted or unsubstituted morpholine, an alkali metal hydroxide, or a tri-lower alkyl amine.
  • the base may comprise a basic reagent selected from 4- methylmorpholine, sodium hydroxide, potassium hydroxide, trimethylamine, or triethy) amine.
  • the reaction mixture, in step 2 of the isolation of either enantiomer of t zreo-methylphenidate is cooled to a temperature range of room temperature to 0 °C.
  • the enantiomeric enrichment achieved by the subject invention is 90%, 95%, 99% or even 99.5%.
  • the aqueous base used in step 2 of the isolation of either enantiomer of t/zreo-methylphenidate is selected from ammonium hydroxide, sodium hydroxide or potassium hydroxide.
  • step 3 of the isolation of either enantiomer of t/zreo- methylphenidate converts the respective single enantiomer of t/zreo-methylphenidate into a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is a hydrochloride salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour effectuer le dédoublement direct de thréo-méthylphénidate racémique. Ledit procédé consiste à : former un sel diastéréomérique de thréo-méthylphénidate et un énantiomère unique d'acide di-p-toluoyltartarique ; et cristalliser un des diastéréomères. Le diastéréomère ainsi formé peut être facilement transformé en tout autre sel pharmaceutiquement acceptable.
PCT/US2002/032658 2001-10-12 2002-10-11 Dedoublement direct de chlorhydrate de threo-methylphenidate racemique Ceased WO2003031411A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002353803A AU2002353803A1 (en) 2001-10-12 2002-10-11 Direct resolution of racemic threo-methylphenidate hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32872201P 2001-10-12 2001-10-12
US60/328,722 2001-10-12

Publications (2)

Publication Number Publication Date
WO2003031411A2 true WO2003031411A2 (fr) 2003-04-17
WO2003031411A3 WO2003031411A3 (fr) 2003-07-24

Family

ID=23282136

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/032658 Ceased WO2003031411A2 (fr) 2001-10-12 2002-10-11 Dedoublement direct de chlorhydrate de threo-methylphenidate racemique

Country Status (2)

Country Link
AU (1) AU2002353803A1 (fr)
WO (1) WO2003031411A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008125914A3 (fr) * 2007-01-05 2009-06-11 Archimica Inc Procédé de résolution énantiomérique de d,l-(+)-thréo-méthylphénidate
WO2015069507A1 (fr) * 2013-11-08 2015-05-14 Noramco, Inc. Procédé de préparation méthylphénidate et de sels de qualité pharmaceutique de celui-ci
CN110878021A (zh) * 2019-12-05 2020-03-13 济南大学 一种酒石酸衍生物的制备方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX9805870A (fr) * 1996-01-22 1999-01-31
US6100401A (en) * 1998-04-20 2000-08-08 Novartris Ag Process for preparing the d-threo isomer of methylphenidate hydrochloride

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008125914A3 (fr) * 2007-01-05 2009-06-11 Archimica Inc Procédé de résolution énantiomérique de d,l-(+)-thréo-méthylphénidate
US7897777B2 (en) 2007-01-05 2011-03-01 Archimica, Inc. Process of enantiomeric resolution of D,L-(±)-threo-methylphenidate
WO2015069507A1 (fr) * 2013-11-08 2015-05-14 Noramco, Inc. Procédé de préparation méthylphénidate et de sels de qualité pharmaceutique de celui-ci
CN110878021A (zh) * 2019-12-05 2020-03-13 济南大学 一种酒石酸衍生物的制备方法和用途

Also Published As

Publication number Publication date
WO2003031411A3 (fr) 2003-07-24
AU2002353803A1 (en) 2003-04-22

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