US20120010412A1 - Process for the Synthesis of Substituted Morphinans - Google Patents

Process for the Synthesis of Substituted Morphinans Download PDF

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Publication number
US20120010412A1
US20120010412A1 US13/096,679 US201113096679A US2012010412A1 US 20120010412 A1 US20120010412 A1 US 20120010412A1 US 201113096679 A US201113096679 A US 201113096679A US 2012010412 A1 US2012010412 A1 US 2012010412A1
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US
United States
Prior art keywords
optionally substituted
compound
formula
aryl
halogen
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.)
Abandoned
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US13/096,679
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English (en)
Inventor
Scott Duncan
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.)
Alkermes Pharma Ireland Ltd
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Alkermes 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 Alkermes Inc filed Critical Alkermes Inc
Priority to US13/096,679 priority Critical patent/US20120010412A1/en
Assigned to ALKERMES, INC. reassignment ALKERMES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DUNCAN, SCOTT
Assigned to MORGAN STANLEY SENIOR FUNDING, INC. reassignment MORGAN STANLEY SENIOR FUNDING, INC. PATENT SECURITY AGREEMENT (FIRST LIEN) Assignors: ALKERMES CONTROLLED THERAPEUTICS INC., ALKERMES PHARMA IRELAND LIMITED, ALKERMES, INC.
Assigned to MORGAN STANLEY SENIOR FUNDING, INC. reassignment MORGAN STANLEY SENIOR FUNDING, INC. PATENT SECURITY AGREEMENT (SECOND LIEN) Assignors: ALKERMES CONTROLLED THERAPEUTICS INC., ALKERMES PHARMA IRELAND LIMITED, ALKERMES, INC.
Publication of US20120010412A1 publication Critical patent/US20120010412A1/en
Assigned to ALKERMES PHARMA IRELAND LIMITED reassignment ALKERMES PHARMA IRELAND LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALKERMES, INC.
Assigned to ALKERMES, INC., ALKERMES CONTROLLED THERAPEUTICS INC., ALKERMES PHARMA IRELAND LIMITED reassignment ALKERMES, INC. RELEASE BY SECURED PARTY (SECOND LIEN) Assignors: MORGAN STANLEY SENIOR FUNDING, INC.
Priority to US14/199,371 priority patent/US10005790B2/en
Priority to US15/988,498 priority patent/US10155772B2/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified.
  • Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body.
  • Step 5 relates to the conversion of a compound of formula IE or a salt or hydrate thereof to a compound of formula I or a salt or hydrate thereof.
  • Step 3 relates to the conversion of a compound of formula IC or a salt or hydrate thereof to a compound of formula ID or a salt or hydrate thereof:
  • the preferred Pd(0) catalyst is generated in situ from Pd(OAc) 2 or PdCl 2 and 1,1′-bis(diphenylphosphino)-ferrocene.
  • the invention relates to a method further comprising the step of reacting a compound of Formula IVB with a cyanide to produce a compound of Formula IVC:
  • alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions.
  • the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for “substituted” or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively.
  • Preferred lower alkenyl radicals include 2 to about 6 carbon atoms (“C 2 -C 6 ”).
  • alkenyl and “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • cycloalkenyl refers to partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • heterocyclyl refers to saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy
  • reaction vessel under inert atmosphere was charged with t-Butanol (60 L), sodium chloride (12 kg) and Compound-15 (6000 g). Potassium hydroxide (KOH; 2986 g) was added and the reaction mixture was heated to 8° C. Upon reaction completion as judged by HPLC, the reaction mixture was cooled to 20° C. to 30° C. 2-Methyltetrahydrofuran (2-Me-THF; 72 L, 12 vol.) was added to the reaction mixture. The reactor was charged with 15% brine solution (60 L) and stirred for a minimum of 20 minutes. The layers were separated and the aqueous layer was further extracted with 2-Me-THF (30 L, 5 vol.).
  • reaction vessel under inert atmosphere was charged with reverse osmosis/deionized water (75 L) and Hydrochloric acid, 37% ACS grade (8 L). The contents were cooled and Compound-22 (5000 g) and Toluene (50 L) were added. The biphasic mixture was heated to 80° C. Upon reaction completion as judged by HPLC, the reaction mixture was cooled to 15° C. to 20° C. The layers were separated and dichloromethan (DCM; 25 L) was added to the aqueous layer and the mixture was stirred for a minimum of 15 minutes. Separate the layers and filter the aqueous mixture into a clean vessel and cool the filtrate to 0° C.
  • DCM dichloromethan

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Addiction (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
US13/096,679 2010-07-08 2011-04-28 Process for the Synthesis of Substituted Morphinans Abandoned US20120010412A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US13/096,679 US20120010412A1 (en) 2010-07-08 2011-04-28 Process for the Synthesis of Substituted Morphinans
US14/199,371 US10005790B2 (en) 2010-07-08 2014-03-06 Process for the synthesis of substituted morphinans
US15/988,498 US10155772B2 (en) 2010-07-08 2018-05-24 Process for the synthesis of substituted morphinans

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36238810P 2010-07-08 2010-07-08
US13/096,679 US20120010412A1 (en) 2010-07-08 2011-04-28 Process for the Synthesis of Substituted Morphinans

Related Child Applications (1)

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US14/199,371 Continuation US10005790B2 (en) 2010-07-08 2014-03-06 Process for the synthesis of substituted morphinans

Publications (1)

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US20120010412A1 true US20120010412A1 (en) 2012-01-12

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US13/096,679 Abandoned US20120010412A1 (en) 2010-07-08 2011-04-28 Process for the Synthesis of Substituted Morphinans
US14/199,371 Active 2032-01-01 US10005790B2 (en) 2010-07-08 2014-03-06 Process for the synthesis of substituted morphinans
US15/988,498 Active US10155772B2 (en) 2010-07-08 2018-05-24 Process for the synthesis of substituted morphinans

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US15/988,498 Active US10155772B2 (en) 2010-07-08 2018-05-24 Process for the synthesis of substituted morphinans

Country Status (8)

Country Link
US (3) US20120010412A1 (es)
EP (1) EP2590649B1 (es)
JP (1) JP5728084B2 (es)
AU (1) AU2011276978B2 (es)
CA (1) CA2804940C (es)
ES (1) ES2708726T3 (es)
NZ (1) NZ605234A (es)
WO (1) WO2012005795A1 (es)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8946255B2 (en) 2012-12-28 2015-02-03 Purdue Pharma L.P. Substituted morphinans and the use thereof
WO2015099863A1 (en) * 2013-12-27 2015-07-02 Purdue Pharma L.P. 6-substituted and 7-substituted morphinan analogs and the use thereof
US9119848B2 (en) 2009-12-04 2015-09-01 Alkermes Pharma Ireland Limited Morphinan derivatives for the treatment of drug overdose
US9126977B2 (en) 2010-08-23 2015-09-08 Alkermes Pharma Ireland Limited Methods for treating antipsychotic-induced weight gain
US9133125B2 (en) 2013-05-24 2015-09-15 Alkermes Pharma Ireland Limited Morphan and morphinan analogues, and methods of use
US9211293B2 (en) 2011-12-15 2015-12-15 Alkermes Pharma Ireland Limited Opioid agonist antagonist combinations
US9656961B2 (en) 2013-05-24 2017-05-23 Alkermes Pharma Ireland Limited Methods for treating depressive symptoms
US11707466B2 (en) 2020-11-12 2023-07-25 Alkermes Pharma Ireland Limited Immediate release multilayer tablet

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10316042B2 (en) 2012-07-16 2019-06-11 Rhodes Technologies Process for improved opioid synthesis
KR101946104B1 (ko) 2012-07-16 2019-02-08 로드스 테크놀로지즈 개선된 오피오이드 합성을 위한 방법
US20160244459A1 (en) 2013-05-24 2016-08-25 Rhodes Technologies Opioid ketal compounds and uses thereof
CA2937006C (en) 2014-01-15 2018-12-04 Rhodes Technologies Process for improved oxycodone synthesis
WO2015107472A1 (en) * 2014-01-15 2015-07-23 Rhodes Technologies Process for improved oxymorphone synthesis
US11247999B1 (en) 2021-07-02 2022-02-15 Joseph DeGraw Facile conversion of morphine to normorphine

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9119848B2 (en) 2009-12-04 2015-09-01 Alkermes Pharma Ireland Limited Morphinan derivatives for the treatment of drug overdose
US9126977B2 (en) 2010-08-23 2015-09-08 Alkermes Pharma Ireland Limited Methods for treating antipsychotic-induced weight gain
US9211293B2 (en) 2011-12-15 2015-12-15 Alkermes Pharma Ireland Limited Opioid agonist antagonist combinations
US8946255B2 (en) 2012-12-28 2015-02-03 Purdue Pharma L.P. Substituted morphinans and the use thereof
US9388162B2 (en) 2012-12-28 2016-07-12 Purdue Pharma L.P. Substituted morphinans and the use thereof
US9656961B2 (en) 2013-05-24 2017-05-23 Alkermes Pharma Ireland Limited Methods for treating depressive symptoms
US9133125B2 (en) 2013-05-24 2015-09-15 Alkermes Pharma Ireland Limited Morphan and morphinan analogues, and methods of use
US9416137B2 (en) 2013-05-24 2016-08-16 Alkermes Pharma Ireland Limited Morphan and morphinan analogues, and methods of use
US9682936B2 (en) 2013-05-24 2017-06-20 Alkermes Pharma Ireland Limited Morphan and morphinan analogues, and methods of use
US10231963B2 (en) 2013-05-24 2019-03-19 Alkermes Pharma Ireland Limited Methods for treating depressive symptoms
US10287250B2 (en) 2013-05-24 2019-05-14 Alkermes Pharma Ireland Limited Morphan and morphinan analogues, and methods of use
US10736890B2 (en) 2013-05-24 2020-08-11 Alkermes Pharma Ireland Limited Methods for treating depressive symptoms
US10752592B2 (en) 2013-05-24 2020-08-25 Alkermes Pharma Ireland Limited Morphan and morphinan analogues, and methods of use
US11534436B2 (en) 2013-05-24 2022-12-27 Alkermes Pharma Ireland Limited Methods for treating depressive symptoms
WO2015099863A1 (en) * 2013-12-27 2015-07-02 Purdue Pharma L.P. 6-substituted and 7-substituted morphinan analogs and the use thereof
US10550088B2 (en) 2013-12-27 2020-02-04 Purdue Pharma L.P. 6-substituted and 7-substituted morphinan analogs and the use thereof
US11707466B2 (en) 2020-11-12 2023-07-25 Alkermes Pharma Ireland Limited Immediate release multilayer tablet
US11951111B2 (en) 2020-11-12 2024-04-09 Alkermes Pharma Ireland Limited Immediate release multilayer tablet

Also Published As

Publication number Publication date
CA2804940A1 (en) 2012-01-12
JP5728084B2 (ja) 2015-06-03
NZ605234A (en) 2015-02-27
EP2590649A4 (en) 2014-01-29
EP2590649B1 (en) 2018-11-28
EP2590649A1 (en) 2013-05-15
US20180334464A1 (en) 2018-11-22
ES2708726T3 (es) 2019-04-10
AU2011276978B2 (en) 2015-01-29
WO2012005795A1 (en) 2012-01-12
US20140303371A1 (en) 2014-10-09
AU2011276978A1 (en) 2013-01-17
CA2804940C (en) 2017-03-07
US10155772B2 (en) 2018-12-18
JP2013533876A (ja) 2013-08-29
US10005790B2 (en) 2018-06-26

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