US20070232808A1 - Process for preparing heterocyclic derivatives - Google Patents

Process for preparing heterocyclic derivatives Download PDF

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Publication number
US20070232808A1
US20070232808A1 US11/693,757 US69375707A US2007232808A1 US 20070232808 A1 US20070232808 A1 US 20070232808A1 US 69375707 A US69375707 A US 69375707A US 2007232808 A1 US2007232808 A1 US 2007232808A1
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US
United States
Prior art keywords
alkyl
compounds
alkoxy
group
halo
Prior art date
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Abandoned
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US11/693,757
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English (en)
Inventor
Sergio Bacchi
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Glaxo Group Ltd
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Glaxo Group Ltd
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Filing date
Publication date
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Assigned to GLAXO GROUP LIMITED reassignment GLAXO GROUP LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BACCHI, SERGIO
Publication of US20070232808A1 publication Critical patent/US20070232808A1/en
Priority to US12/608,184 priority Critical patent/US7838680B2/en
Assigned to GLAXO GROUP LIMITED reassignment GLAXO GROUP LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BACCHI, SERGIO
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel process, useful for preparing key intermediates in the synthesis of various compounds, among them compounds which are potent and specific antagonists of D3 receptors.
  • the present invention relates to a novel process for preparing thiazole or triazole derivatives of formula (I)
  • C1-C6 alkyl refers to a linear or branched alkyl group containing from 1 to 6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • halo C1-C6 alkyl means an alkyl group having one or more carbon atoms and wherein at least one hydrogen atom is replaced with halogen such as for example a trifluoromethyl group and the like.
  • C1-C6 thioalkyl may be a linear or a branched chain thioalkyl group, for example thiomethyl, thioethyl, thiopropyl, thioisopropyl, thiobutyl, thiosec-butyl, thiotert-butyl and the like.
  • C2-C6 alkenyl defines straight or branched chain hydrocarbon radicals containing one or more double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl and the like.
  • C1-C6 alkoxy group may be a linear or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.
  • halo C1-C6 alkoxy group may be a C1-C6 alkoxy group as defined before substituted with at least one halogen, preferably fluorine, such as OCHF 2 , or OCF 3 .
  • C2-C6 alkynyl defines straight or branched chain hydrocarbon radicals containing one or more triple bond and having from 2 to 6 carbon atoms including acetylenyl, propynyl, 1-butynyl, 1-pentynyl, 3-methyl-1-butynyl and the like.
  • aryl means an aromatic carbocyclic moiety such as phenyl, biphenyl or naphthyl.
  • heteroaryl means an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono-and bicyclic ring systems.
  • heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, quinazolinyl, and benzodioxolyl.
  • 5-6 membered heterocycle means, according to the above definition, a 5-6 monocyclic heterocyclic ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
  • Heterocycles include heteroaryls as defined above. The heterocycle may be attached via any heteroatom or carbon atom.
  • the term includes (but is not limited to) morpholinyl, pyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • HOBt and its by-products have an explosive nature and DCC and its by-product are always difficult to fully remove.
  • the process solves the above problems by using n-propane phosphonic cyclic anhydride, T3P, as condensation agent.
  • T3P was first used in the peptide synthesis in 1980 by H. Wissmann (Angew. Chem., 1980, 92, 129) and is steadily gaining importance in organic synthesis because is less toxic and safer compared to other common condensation agents, such as DCC.
  • T3P is used as 50% solution in ethyl acetate in the process of the present invention and does not need the isolation of the intermediate hydrazine-carbothiamide.
  • T3P is available as 50% solution in DMF (dimethylformamide) and may be employed in the process of the present invention.
  • the starting material, the heterocyclic carboxylic acid, generally commercially available or which may be prepared according to known methods in the literature, in an amount of 1 equivalent may be conveniently dissolved in the appropriate solvent (for example dimethylformamdide; ethyl acetate; acetonitrile and tetrahydrofurane and other polar aprotic solvent) and treated with a slightly excess of derivatives of 3-thiosemicarbazide (1.10 eq), such as 4-methyl derivative. Then an organic base (e.g. triethylamine, diisopropylethylamine and possibly other aliphatic of aromatic amines) is added at RT.
  • the appropriate solvent for example dimethylformamdide; ethyl acetate; acetonitrile and tetrahydrofurane and other polar aprotic solvent
  • derivatives of 3-thiosemicarbazide (1.10 eq)
  • an organic base e.g. triethylamine
  • N-propane phosphonic cyclic anhydride (50% w/w in ethyl acetate) may be then added at a temperature ranging from 0 to 40 degrees dropwise. In case the addition is made at about 0° C., the temperature is then maintained below 15° C. over 20-60 minutes. The resulting mixture was then stirred at 20° C. for 2-16 hours.
  • the mixture is then diluted with an aqueous solution of an appropriate inorganic base until basic pH was reached.
  • the suitable base may be selected among: potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide.
  • the resulting bi-phasic mixture (when observed) is then allowed separating and the upper organic layer discarded.
  • the aqueous layer is then heated to 50-90° C. (internal temperature) for half an hour to several hours until reaction completion.
  • an appropriate mineral acid e.g. HCl 37%) is then slowly added to adjust the pH as needed. (4 to 8).
  • the suspension is then generally stirred for 2-16 hours, then the solid was filtered, washed with pure water and dried in a vacuum oven at 40-60° C. until dryness.
  • the final product is isolated from the aqueous mixture uncontaminated by phosphorous derivatives.
  • Step 1 Time-Reserv.A-Reserv.B Time 0 min 100%
  • Step 2 Time-Reserv.A-Reserv.B Time 8 min 5%
  • Step 3 Time-Reserv.A-Reserv.B Time 8.01 min 100%
  • the mixture was diluted with NaOH 4 M (120.0 mL). The resulting bi-phasic mixture was allowed separating and the upper organic layer discarded.
  • the suspension was stirred for 8 hours, then the solid was filtered and washed with water (60 mL), and it was dried in a vacuum oven at 40° C. overnight.
  • the suspension was cooled to 5° C. and the solid was filtered and washed with water, and it was then dried in a vacuum oven at 40° C. overnight.
  • the solid was filtered and it was then dried in a vacuum oven at 40° C. overnight.
  • the solid was filtered and washed with water (3 times with 20 mL), and it was then dried in a vacuum oven at 40° C. overnight.
  • mixture was allowed to reach ambient temperature and stirred for 2 hours under nitrogen.
  • the pH of the mixture was checked over time and pH adjusted to 12 if necessary. The heating was kept for a total amount of 3 hours.
  • the mixture was filtered, the cake washed with 22.5 mL of water and the collected solid dried under vacuum oven at 40° C. for 5 hours.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Steroid Compounds (AREA)
US11/693,757 2006-04-03 2007-03-30 Process for preparing heterocyclic derivatives Abandoned US20070232808A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/608,184 US7838680B2 (en) 2006-04-03 2009-10-29 Process for preparing heterocyclic derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0607899.2 2006-04-03
GBGB0607899.2A GB0607899D0 (en) 2006-04-03 2006-04-03 Process for preparing heterocyclic derivatives

Related Child Applications (1)

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US12/608,184 Continuation US7838680B2 (en) 2006-04-03 2009-10-29 Process for preparing heterocyclic derivatives

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US20070232808A1 true US20070232808A1 (en) 2007-10-04

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US11/693,757 Abandoned US20070232808A1 (en) 2006-04-03 2007-03-30 Process for preparing heterocyclic derivatives
US12/608,184 Expired - Fee Related US7838680B2 (en) 2006-04-03 2009-10-29 Process for preparing heterocyclic derivatives

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Country Status (18)

Country Link
US (2) US20070232808A1 (es)
EP (1) EP2007747B1 (es)
JP (1) JP5167242B2 (es)
KR (1) KR101411124B1 (es)
CN (1) CN101454308B (es)
AU (1) AU2007233744B2 (es)
BR (1) BRPI0710049A2 (es)
CA (1) CA2648089A1 (es)
CR (1) CR10351A (es)
EA (1) EA017304B1 (es)
ES (1) ES2443219T3 (es)
GB (1) GB0607899D0 (es)
IL (1) IL194389A0 (es)
MA (1) MA30354B1 (es)
MX (1) MX2008012876A (es)
NO (1) NO20084414L (es)
WO (1) WO2007113261A1 (es)
ZA (1) ZA200808107B (es)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018189340A1 (en) 2017-04-14 2018-10-18 Italfarmaco S.P.A. Selective hdac6 inhibitors
WO2022029041A1 (en) 2020-08-07 2022-02-10 Italfarmaco S.P.A. 2-(4-((5-(benzo[b]thiophen-3-yl)-1h-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole derivatives and similar compounds as selective inhibitors of histone deacetylase 6 (hdac6) for use in treating e.g. peripheral neuropathy

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MD3995C2 (ro) * 2009-05-11 2010-07-31 Государственный Университет Молд0 Utilizare a di(µ-Ofenoxi)-di{[2-(4-aminobenzensulfamido)-5-etil-1,3,4-tiadiazol]-3,5-dibromosalicilidentiosemicarbazonato(-1)-cupru} în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar
CN106866657A (zh) * 2017-04-25 2017-06-20 成都倍特药业有限公司 一种麦角新碱的制备方法
US9862675B1 (en) 2017-07-05 2018-01-09 King Fahd University Of Petroleum And Minerals Method of N-formylating amines with a phosphonic anhydride

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020032238A1 (en) * 2000-07-08 2002-03-14 Henning Priepke Biphenylcarboxylic acid amides, the preparation thereof and the use thereof as medicaments

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10033337A1 (de) * 2000-07-08 2002-01-17 Boehringer Ingelheim Pharma Biphenylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2002032238A2 (en) * 2000-10-20 2002-04-25 Messmer, Ludwig Highly compressed filter tow bales
DK1745040T3 (da) * 2004-02-23 2010-04-12 Glaxo Group Ltd Som modulatorer af dopamin-D3-receptorer anvendelige azabicyclo(3.1.0)hexanederivater
GB0517193D0 (en) 2005-08-22 2005-09-28 Glaxo Group Ltd Novel use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020032238A1 (en) * 2000-07-08 2002-03-14 Henning Priepke Biphenylcarboxylic acid amides, the preparation thereof and the use thereof as medicaments

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018189340A1 (en) 2017-04-14 2018-10-18 Italfarmaco S.P.A. Selective hdac6 inhibitors
US11351178B2 (en) 2017-04-14 2022-06-07 Italfarmaco Spa Selective HDAC6 inhibitors
WO2022029041A1 (en) 2020-08-07 2022-02-10 Italfarmaco S.P.A. 2-(4-((5-(benzo[b]thiophen-3-yl)-1h-tetrazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole derivatives and similar compounds as selective inhibitors of histone deacetylase 6 (hdac6) for use in treating e.g. peripheral neuropathy

Also Published As

Publication number Publication date
JP5167242B2 (ja) 2013-03-21
GB0607899D0 (en) 2006-05-31
US20100048895A1 (en) 2010-02-25
IL194389A0 (en) 2009-08-03
EA017304B1 (ru) 2012-11-30
JP2009532428A (ja) 2009-09-10
MX2008012876A (es) 2008-10-13
CN101454308A (zh) 2009-06-10
BRPI0710049A2 (pt) 2011-08-02
CR10351A (es) 2008-10-29
CN101454308B (zh) 2013-05-08
WO2007113261A1 (en) 2007-10-11
EP2007747B1 (en) 2013-11-20
CA2648089A1 (en) 2007-10-11
EP2007747A1 (en) 2008-12-31
US7838680B2 (en) 2010-11-23
KR20080108328A (ko) 2008-12-12
AU2007233744A1 (en) 2007-10-11
KR101411124B1 (ko) 2014-06-25
ES2443219T3 (es) 2014-02-18
MA30354B1 (fr) 2009-04-01
NO20084414L (no) 2008-10-28
AU2007233744B2 (en) 2012-09-06
ZA200808107B (en) 2009-10-28
EA200870405A1 (ru) 2009-04-28

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Effective date: 20070503